Are You Confident of the Diagnosis?
What you should be alert for in the history
Characteristic findings on physical examination
Expected results of diagnostic studies [histopathology, serologic tests, genetic tests, imaging studies]
Diagnosis confirmation [Describe those conditions in the differential diagnosis that may reasonably mimic the diagnosis and explain their distinction]
Pemphigus foliaceus (PF) and its endemic forms (including fogo selvagem) are autoimmune skin blistering diseases that are identical histologically and have a similar clinical presentation, differing primarily in their epidemiology.
What you should be alert for in the history
Determine the scope of cutaneous disease. Ask about aggravating factors, which can include stress, ultraviolet radiation, menses, recent vaccinations, or cessation of smoking.
Ask about travel to areas with endemic PF, such as rural Brazil or Tunisia.
Although rare, determine if any underlying factors may be present. Ask about recent changes in medications. Ask about trouble speaking or swallowing, eyelid droop, or double vision (the earliest signs of myasthenia gravis). In children, ask about cough, chest pain, hoarseness, or difficulty swallowing (symptoms of thymoma; thymoma in adults is usually asymptomatic early on.)
Characteristic findings on physical examination
Scalp, face, trunk, and extremities are commonly affected. Skin blisters are rarely intact, more often presenting with “cornflake crust” erosions that can be mistaken for impetigo, seborrheic dermatitis, tinea capitis, or eczema (Figure 1).
Patients with widespread disease may demonstrate the Nikolsky sign, 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 PF and may also be observed in other skin blistering diseases such as staphylococcal scalded skin syndrome, pemphigus vulgaris, 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. PF will show acantholysis (loss of intercellular adhesion between intact keratinocytes) in the granular or subcorneal layer of the epidermis (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.
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. PF will demonstrate IgG cell surface staining of keratinocytes. IgA may also be positive. C3 is rarely positive. 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 PF sera with monkey esophagus (a common substrate for pemphigus vulgaris testing) is often negative. Similar to DIF, IIF for PF will demonstrate IgG cell surface staining (Figure 3), 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 for PF. 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. In endemic forms of PF, healthy relatives of patients may also demonstrate positive desmoglein 1 ELISA index values.
The clinical differential diagnosis for PF can include bullous impetigo, staphylococcal scalded skin syndrome, seborrheic dermatitis, tinea capitis, herpes simplex or zoster, eczema, necrolytic migratory erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and other rare autoimmune blistering diseases.
Who is at Risk for Developing this Disease?
The incidence of PF is difficult to determine, as most studies have examined both pemphigus vulgaris and pemphigus foliaceus. In Western Europe, the incidence of PF is 0.5 to 1 per million per year, typically appearing in older adults.
Foci of endemic PF have been described in rural Brazil (fogo selvagem, “wild fire” in Portuguese), Tunisia, and Colombia. Fogo selvagem is the best characterized of the endemic forms of PF. The yearly incidence of fogo selvagem in Brazil ranges from 0.8 to 4.0 per thousand; the prevalence is as high as 3.4%. Onset begins in adolescence, with a slightly higher incidence in women (60% of cases). In Tunisia, the incidence of endemic PF is 6.6 per million per year, primarily occurring in young women. The prevalence of endemic PF in El Bagre, Colombia is 4.7%, and occurs mainly in older men. Colombian endemic PF has clinical overlap with pemphigus erythematosus, with a positive lupus band test on direct immunofluorescence in 40% of cases.
Although rare, PF has been associated with both myasthenia gravis and thymoma. It is more common for patients with thymoma to have pemphigus than for patients with pemphigus to have thymoma.
Penicillamine and captopril have been associated with PF. 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?
Pemphigus foliaceus (both endemic and sporadic) is caused by autoantibodies against desmoglein 1. Desmoglein 1 is a transmembrane proteins 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 foliaceus are unknown, although the existence of endemic forms of disease holds clues to understanding how autoimmunity can be triggered in select populations. The geographic distribution of fogo selvagem cases is similar to that of the black fly Simulium nigrimanum, and one study found the bite of the black fly to be significantly more frequent among those with fogo selvagem compared to a control population with unrelated dermatoses.
In rural areas of Brazil, up to 55% of unaffected individuals have a low-level IgG1 antibody response against desmoglein 1, and 58% demonstrate anti-desmoglein 1 IgM. 40-80% of patients from Brazil with the vector-borne diseases onchocerciasis, Leishmania, and Chagas disease also demonstrate low-level anti-desmoglein 1 antibodies. PF and fogo selvagem patients demonstrate nonpathogenic anti-desmoglein 1 IgG1 in addition to IgG4 pathogenic autoantibodies, the latter of which disappear from the circulation with disease remission. Current leading theory suggests that an infectious or other environmental agent may trigger an autoantibody response, which subsequently becomes pathogenic by intramolecular epitope spreading in genetically susceptible individuals.
Most pathogenic antibodies target the desmoglein extracellular domain that is predicted to form the trans-adhesive 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
Pemphigus foliaceus only affects the skin and thus is rarely associated with systemic complications. However, patients can develop severe blistering, leading to risk of sepsis.
Pemphigus foliaceus is rarely associated with thymoma or myasthenia gravis. Myasthenia gravis would be best evaluated by a neurologist, who can complete a full neurologic examination and may test for serum acetylcholine receptor autoantibodies. Posteroanterior and lateral chest radiographs with or without computerized tomography follow up can detect most thymomas. Thymic irradiation or removal, although beneficial for myasthenia gravis, may not lead to remission of pemphigus.
Treatment options are summarized in Table I.
|Tetracyclines plus niacinamide|
Optimal Therapeutic Approach for this Disease
Class I steroids such as clobetasol can be applied twice daily to new blisters and erosions on both the face and body. Topical tacrolimus ointment may also be helpful, particularly for lesions on the face where chronic steroid therapy is undesirable. For mild disease (transient lesions that heal within 1 week), monotherapy with topical corticosteroids 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 corticosteroids such as prednisone may be necessary. For moderate disease, 0.5mg/kg/day of prednisone or equivalent may be sufficient. Doses generally do not need to exceed 1mg/kg/day of prednisone. If patients flare on 1mg/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 (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, and there is a small long-term risk of lymphoma and fatal infection or reactivation from JC virus with progressive multifocal leukencephalopathy. Reduction of corticosteroid dose can be initiated as early as 1 month after starting mycophenolate mofetil, although maximal effect 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 effects, therapeutic effect, or the target dose of 2.5mg/kg/day occurs. Measurement of serum thiopurine methyltransferase (TPMT) level prior to start of azathioprine therapy can be performed, although some studies suggest that TPMT levels do not correlate with the incidence of adverse effects or 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 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.
In patients who have severe or persistent disease that cannot be controlled with corticosteroids and/or other immunosuppressives, other therapies such as rituximab, intravenous immunoglobulin, plasmapheresis, and cyclophosphamide can be considered.
B-cell depletion therapy with rituximab (anti-CD20 monoclonal antibody) is an effective therapy for PF. Both lymphoma (375 mg/m2 IV weekly x 4 weeks) and rheumatoid arthritis (1000mg IV on days 1 and 15) dosing regimens can be used. In vivo studies from lymphoma patients indicate that peripheral blood B cells disappear from the circulation within days, although antibody production by plasma cells (which are not well targeted by rituximab) can persist for months; therefore maximal results are not observed until 3-6 months after infusion, and re-infusion every 6 months may be required.
Fatal infection has occurred with rituximab therapy, including bacterial sepsis, hepatitis B reactivation, and progressive multifocal leukencephalopathy from JC virus, although fatal infection is also a potential side effect of first-line therapies, including prednisone and mycophenolate mofetil.
Intravenous immunoglobulin (IVIG, 2mg/kg, divided over 3-5 days) is effective for PF therapy and can be provided by hospital or home infusion. IVIG induces catabolism of endogenous serum antibodies and offers the advantage of being immunoprotective. A disadvantage of IVIG is that the temporary serum viscosity associated with the infusion can cause stroke or other complications from clotting. The serum half life of IVIG has been reported to range from 8-39 days (average 3-4 weeks). Treatment guidelines for autoimmune blistering disease with IVIG suggest an initial frequency of every 4 weeks until disease remits, increasing to 6, 8, 10, 12, 14, then 16 weeks, the latter being the proposed end point for an initial course of therapy.
Plasmapheresis allows for the rapid removal of antibodies from the circulation, but must always be used in conjunction with adjunctive immunosuppressants to prevent new antibody production.
Cyclophosphamide (50-200mg daily) is among the fastest agents for treating pemphigus. However, its risk of blood count and liver test abnormalities, infertility, and hemorrhagic cystitis with bladder carcinoma, together with the advent of other effective therapies such as rituximab, have led to the decreased use of cyclophosphamide in the management of PF.
The goal of treatment is to obtain a complete remission off therapy, although many patients may only achieve a partial remission off therapy, or a complete remission on minimal therapy. When starting patients on therapy, risks of medications should be discussed. There is no systemic medication for PF that is 100% safe. Retrospective studies suggest that PF is fatal in approximately 60% of patients, particularly in elderly patients with concurrent medical problems. However, many PF patients do not develop severe or progressive disease. Therefore, the decision on how aggressive to be with systemic immunosuppressive therapy should be made on an individual basis.
Open erosions can become superinfected with Staphylococcus 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 and use of massage or other high pressure showerheads should be avoided.
Patients should ideally be maintained in complete remission for at least 1 year before all immunosuppressive therapy is discontinued. Often patients want to taper off their medications quickly, but then flare and have to go back on high doses of medications for disease control, which may reduce the chance for disease remission. Typically, corticosteroids are tapered off first, then adjunctive immunosuppressants are slowly tapered over the course of one year. However, the tapering regimen should be tailored for each patient depending on side effects and response to therapy. It is common for patients to have a small flare with each dose taper; as long as lesions heal within 1 week and no further lesions form, the taper can be continued.
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 (e.g. nasal influenza or zoster.)
Unusual Clinical Scenarios to Consider in Patient Management
Pregnant patients with PF should be referred for high-risk obstetrical care. Pregnant patients 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 drug 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.
In hospitalized patients with severe disease, blood should be cultured so that bacteremia can be identified and treated. A thin layer of triamcinolone 0.1% ointment can be spread on sterile linens and wrapped around patients twice daily. Unfortunately, there is no single consensus regimen among experts about how to treat severe pemphigus, owing to the sparsity of randomized controlled trials in this rare disease. Historically, these patients were treated with corticosteroids, cyclophosphamide, and plasmapheresis due to their rapid therapeutic effect. Several other regimens can be considered for the hospitalized patient, including:
-intravenous corticosteroids (as high as 60mg methylprednisolone four times daily), adjunctive immunosuppressant such as mycophenolate mofetil, and IVIG (which is immunoprotective)
-intravenous corticosteroids (+/- adjunctive immunosuppressant) and rituximab for long-term control
-intravenous corticosteroids (+/- adjunctive immunosuppressant), plasmapheresis to immediately remove serum antibodies, followed by rituximab for long term control
The timing of certain combinations of medications should be considered. For example, rituximab infusion should not be administered immediately before plasmapheresis or IVIG, as the former would clear the rituximab and the latter may induce its catabolism. However, rituximab is thought to rapidly bind and deplete circulating B cells (within days), and peripheral B cell counts begin to recover 8 days after infusion.
Theoretically therefore, plasmapheresis and IVIG could be considered as early as 1-4 weeks after completion of rituximab infusion, although studies indicate that rituximab half-life progressively increases with subsequent weekly infusions (suggesting saturation of in vivo binding sites), and that a higher serum concentration is associated with better treatment outcome in B cell lymphomas. Conversely, plasmapheresis can be performed immediately prior to rituximab, but the ideal timing of rituximab infusion after a course of IVIG is unknown, with recommendations ranging from 1-6 weeks based on the serum half life of IVIG.
What is the Evidence?
Payne, AS, Stanley, JR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, B, Paller, AS, Leffell, DJ. “Pemphigus”. Dermatology in general medicine. 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, Bystryn, JC. “Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus”. J Am Acad Dermatol. vol. 58. 2008. pp. 1043-6. (An international consensus of definitions for disease endpoints [such as remission, relapse, and treatment failure].)
Li, N, Aoki, V, Hans-Filho, G, Rivitti, EA, Diaz, LA. “The role of intramolecular epitope spreading in the pathogenesis of endemic pemphigus foliaceus (fogo selvagem)”. J Exp Med. vol. 197. 2003. pp. 1501-10. (This study describes the immunologic characteristics of autoantibodies isolated from fogo selvagem patients in active disease and remission.)
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 seven PF] demonstrated equal efficacy and safety between mycophenolate mofetil [2g daily] and azathioprine [2mg/kg/day] as steroid sparing agents in pemphigus, with a trend toward greater efficacy and safety for mycophenolate mofetil.)
Chams-Davatchi, C, Esmaili, N, Daneshpazhooh, M, Valikhani, M, Balighi, K, Hallaji, Z. “Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris”. J Am Acad Dermatol. vol. 57. 2007. pp. 622-8. (This trial compared prednisolone alone to prednisolone plus azathioprine (2.5mg/kg/day), mycophenolate mofetil, (2g/day) or pulse IV cyclophosphamide among 120 patients with pemphigus vulgaris. All agents were effective as steroid-sparing agents, although azathioprine was associated with a significantly lower mean total prednisolone dose as compared to mycophenolate mofetil.)
Joly, P, Mouquet, H, Roujeau, JC. “A single cycle of rituximab for the treatment of severe pemphigus”. New Engl J Med. vol. 357. 2007. pp. 545-52. (Largest published case series of 21 pemphigus patients treated with rituximab (14 with pemphigus vulgaris and 7 with pemphigus foliaceus). Eighteen patients achieved complete remission within 3 months, and 20 patients achieved complete remission within 12 months. After treatment with corticosteroids or a second cycle of rituximab, 18 patients remained disease-free at 34 months, with eight patients completely off corticosteroid therapy. Two patients had severe complications including pyelonephritis and fatal sepsis.)
Ahmed, AR, Spigelman, Z, Cavacini, LA, Posner, MR. “Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin”. N Engl J Med. vol. 355. 2006. pp. 1772-9. Nine out of 11 pemphigus vulgaris patients had sustained remissions lasting 22-37 months, and the two who relapsed had sustained remissions after a second course of rituximab only. No infections occurred. The authors propose that IVIG replaces the beneficial antibodies otherwise depleted by rituximab. However, the safety and efficacy of the combined regimen compared to rituximab or IVIG alone, as well as the optimal timing of rituximab and IVIG infusions, remains unknown.)
Ahmed, AR, Dahl, MV. “Consensus statment on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases”. Arch Dermatol. vol. 139. 2003. pp. 1051-9. (Provides guidelines for the use of IVIG, including indications, prescreening, premedications, dose, frequency, monitoring, and therapeutic endpoints.)
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