The vesicobullous diseases in dermatology are numerous and quite distinct from one another; the unifying feature, intuitively, is the histologic feature of separation either intraepidermally or subepidermally. Vesicobullous diseases can be mediated through infections, allergic causes, physical insults, or may occur as a result of autoimmune and hereditary disorders. The majority of vesicobullous diseases are acquired, wherein autoantibodies target specific cellular adhesion molecules resulting in separation of keratinocytes. In contrast, inherited vesicobullous diseases due to genetic loss of either adhesion molecules or basic structural proteins, lead to loss of cell-cell adhesion following minor or insignificant trauma or traction to the skin. The term “acantholysis” refers to intraepidermal pathology, whereas “blister” is traditionally used to delineate subepidermal disease. Whether acquired or inherited, vesicobullous diseases are a major source of patient morbidity and mortality in dermatology, either due to inherent disease processes or from therapeutic complications.
Several clinical characteristics including age of onset, family history, exposure history, and known systemic or other dermatologic disease can provide clues as to the etiology of a blistering disease. Advanced clinical recognition of vesicobullous diseases takes lesion morphology, distribution, evolution, and presence of Nikolsky sign into consideration; however, diagnosis strictly relies on histological and immunologic criteria through application of specialized immunohistologic techniques. Despite this clinical armamentarium, blistering diseases are often misdiagnosed and delay in diagnosis or institution of appropriate treatment can sometimes result in death.
INTRAEPIDERMAL BLISTERING DISEASES
Intraepidermal blistering diseases include the acquired pemphigus family and the inherited epidermolysis bullosa simplex. Pemphigus is a group of rare, life-threatening autoimmune blistering diseases characterized by widespread bullae and erosions of the skin and mucous membranes. The pemphigus family can be divided into three major forms: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Other pemphigus subtypes exist such as pemphigus vegetans and Fogo selvagem, all of which will be reviewed in this chapter. Dysfunctional desmosomal proteins leading to acantholysis within the epidermis with subsequent flaccid blister formation characterize the pemphigus family of disorders. Epidermolysis bullosa is a spectrum of inherited and acquired blistering diseases; heritable keratin defects found in Epidermalysis Bullosa Simplex lead to acantholysis and will be discussed in this section, whereas the remainder lead to subepidermal disease and will be discussed later in this chapter.
Before the advent of corticosteroids, pemphigus was associated with a high mortality rate. Today, pemphigus remains a possible dermatologic emergency; however, with new therapeutics, mortality rates have decreased, yet it still conveys significant morbidity. The most classic form of pemphigus is pemphigus vulgaris (PV). PV is also known as “deep” pemphigus, as blisters develop in the deeper portion of the epidermis just above the basal cell layer. Of the entire pemphigus family PV is the most potentially life threatening.
The prevalence of pemphigus vulgaris in men and women is nearly equal and the mean age of onset is 50 to 60 years, although the range is broad and disease arising in the elderly and children has been described. Available data is limited in regards to the incidence of PV, although one review cited an annual incidence of 0.42 per 100,000. In the general population, the incidence ranges from 0.76 to 5 new cases per million per year. However, the incidence is much higher in people of Mediterranean, South Asian, and Jewish ancestry, reported at 16 to 32 cases per million per year. PV is more common than other forms of pemphigus such as pemphigus foliaceus. In Japan with an incidence of 3.5 cases per million per year, the ratio of vulgaris to foliaceus is 2:1, whereas the majority of all cases (73%) are due to vulgaris in France where the incidence is 1.7 cases per million per year.
The exact etiology of PV remains unknown; however, the interaction between environmental factors and genetic background is thought to contribute to its development. Predisposition to PV is linked to genetic factors. For example, certain major histocompatibility complex (MHC) class II molecules, specifically the alleles of human leukocyte antigen DR4 and DRw6, are more common in patients with PV. Despite this, predisposing genetic factors alone may not be sufficient to trigger the autoimmune response seen. Clinical evidence supports the role of dietary factors in the exacerbation of pemphigus. Suspected culprits capable of inducing PV as reported in the literature include thiol compounds (garlic, leek, chives) and phycocyanins (Spirulina platensis alga). Another cause of pemphigus reported in the literature is medications including thiol drugs, phenol drugs, and nonthiol nonphenol drugs. The thiol drugs known to cause pemphigus include captopril, penicillamine, and gold. The phenol group includes culprits such as aspirin, rifampin, levodopa and heroin, while nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and dipyrone are examples of nonthiol nonphenol medications known to induce pemphigus.
In PV, blister formation is associated with IgG antibodies against desmoglein 3 and 1, key adhesion proteins found in both the skin and mucous membranes. Patients with active disease have circulating and tissue-bound autoantibodies of both the immunoglobulin G1 (IgG1) and immunoglobulin G4 (IgG4) subclasses. Autoantibody binding directly interferes with cell-cell adhesion, leading to suprabasilar acantholysis. The target antigen affected—desmoglein 1 or 3 (Dsg1 or Dsg3)—dictates the clinical phenotype seen in pemphigus. For example, individuals with the mucosal-dominant type of PV have only anti-Dsg3 IgG autoantibodies, whereas patients with the mucocutaneous type of PV have both anti-Dsg1 and anti-Dsg3 IgG autoantibodies.
All patients with PV have mucosal membrane erosions, and in 50-70% of patients, the disease begins with the development of oral lesions. In acute PV, patients often present to the ER or their primary care physician complaining of severe dysphagia. On physical exam, there are usually ill-defined erosions of the lips, tongue, buccal mucosa, gingiva or hard/soft palate. Those unfamiliar with PV may diagnose the patient with herpes gingivostomatitis, apthous stomatitis, oral lichen planus, Stevens-Johnson syndrome, or traumatic ulceration. In misdiagnosed and therefore untreated PV, the oral erosions show little or no tendency to heal. This leads to hypoalimentation secondary to patient fear of pain with eating and subsequent malnutrition and unintended weight loss. Other mucous membranes can be involved including the conjunctivae, nasal mucosa, esophagus, vagina, penis and anus. More than half of all patients will also have cutaneous erosions and/or flaccid bullae. Common cutaneous locations include the head, upper torso and intertriginous areas.
In patients with suspected pemphigus vulgaris, a biopsy specimen for routine histology should be obtained from lesional skin. Histology findings in PV include suprabasilar blister formation, acantholysis, and minimal inflammation. In addition to routine histology, a direct immunofluorescence (DIF) of perilesional skin should be obtained against monkey esophagus substrate. An intercellular “fishnet” pattern of IgG antibody and C3 deposition is virtually diagnostic. An indirect immunofluorescence (IIF) is not necessary for diagnosis; however, a baseline is useful before therapy is initiated. Antibody titer usually parallels disease activity in PV, and can be used to track therapeutic response. In the past 10 years, serum enzyme linked immunosorbent assay (ELISA) testing has become widely available for PV and has been shown to be more sensitive than convential IIF. Similar to IIF titers, ELISA values may be used to track disease activity.
As previously mentioned, the diagnosis of PV can be missed, as there are simulators of this disease. The differential diagnosis for pemphigus vulgaris includes distinguishing it from other variants of pemphigus including pemphigus foliaceus and paraneoplastic pemphigus. Additionally, the differential can be divided into two main categories—only oral lesions present versus both oral and cutaneous lesions present. The list of diseases on the former includes aphthous stomatitis, erythema multiforme, herpes simplex, erosive lichen planus, and cicatricial pemphigoid, while the latter differential includes Stevens-Johnson syndrome/toxic epidermal necrolysis, bullous pemphigoid, linear IgA dermatitis, and epidermolysis bullosa acquisita.
Before the advent of corticosteroids in the 1950s, pemphigus vulgaris had been a deadly disease with mortality rates between 90-100% of affected patients within two years of disease onset. Death largely resulted from sepsis secondary to loss of skin barrier, leading to loss of body fluids or serving as a nidus for secondary bacterial infections. PV is almost universally fatal in the absence of therapy, and studies demonstrate higher mortality among the elderly; therefore, early intervention is essential. With the vast array of treatment options available today including systemic glucocorticoids, non-steroidal systemic immunosuppressives, biologics, and immunomodulatory procedures, mortality is now less than 10%.
If the disease appears non-progressive and restricted to one body area such as the mouth, topical therapy alone may be adequate. Corticosteroid gels or ointments such as fluocinonide, desoximetasone, or clobetasol can be initially used two to three times per day Gels are often more easily applied and better tolerated when used within the oral cavity. It should be advised that daily applications should initially occur two to three times per day when symptoms are severe and gradually tapered once relative improvements are seen. Q-tip or fingertip application is recommended, rubbing the gel or ointment onto the affected areas gently for 30 seconds with abstention from food or drink for 30 minutes thereafter. It should also be noted that patient should be aware that these topical therapies are used off-label and products often claim “for external use only.” A prosthetic device such as a dental tray that fits over the teeth and gingiva can be fashioned by a dentist to make application of a topical corticosteroid preparation easier. When these topical medicines are applied under a dental tray their potency is increased. There are few recognized adverse effects associated with the use of topical corticosteroids in the oral cavity including oral candidiasis and reactivation of herpes simplex virus (HSV). The former can be treated with antifungal agents such as clotrimazole lozenges five times per day for one week, nystatin swish and swallow four times per day until the patient is asymptomatic for 48 hours, or oral fluconazole dosed twice weekly. When HSV reactivation occurs, treatment with topical acyclovir six times per day for one week is appropriate with lesions limited to the oral cavity; however, if life threatening HSV reactivation occurs intravenous acyclovir may be necessary.. Intralesional corticosteroid injections can be used in the treatment of PV with some success using triamcinolone 5 to 10mg/mL every two to four weeks.
Excellent oral care is integral in patients with PV. Such care includes gently brushing the teeth twice daily using a soft-bristle toothbrush, daily flossing, and professional teeth cleaning every 3-6 months. Ahmed et al have recommended gentle debridement of necrotic mucosal tissue to prevent infection. Therefore, it is important to have a dentist involved in those patients with PV. Topical analgesics or anesthetics and antiseptic mouthwashes are recommended as further treatment. Various elixirs containing combinations of viscous lidcaine, diphenhydramine, and antacids can be used as an oral rinse to decrease mouth pain. Oral trauma can easily lead to new erosions and should be avoided as much as possible. Poorly fitted dentures, dry crackers, and hard candies have all been implicated in giving rise to trauma of the oral mucosal surface.
Systemic corticosteroids are the mainstay of therapy and often first-line for PV, while immunosuppressive agents are used to aid in disease remission and decrease the need for long –term systemic steroids. The goal of therapy is to control the disease with the lowest possible dose of corticosteroids. Systemic corticosteroid therapy usually in the form of oral prednisone is standard treatment. Therapeutic effects are assessed by the number of new blisters per day, and their rate of healing with gradual tapering of prednisone. Once clinical remission is obtained, changes in the titer of circulating autoantibodies are helpful in estimating the dose of prednisone. Should the disease flare at any point during the attempted taper, patients should return to the steroid dose prior to the disease flare and be maintained at that dose for four weeks before attempting another taper. Patients with PV often require several months of high-dose corticosteroid therapy before a taper can be attempted, irrespective of whether adjuvant therapy is administered. Therefore, patients should be counseled at length on the adverse effects of systemic corticosteroids. Treating physicians should protect against recognized sequelae of prolonged corticosteroid treatment. Such precautions include use of an H2-blocker or proton pump inhibitor for ulcer prophylaxis, as well as a bisphosphonate and calcium with vitamin D supplementation for osteoporosis prophylaxis. Other adverse events to consider include steroid induced glaucoma or elevated intraocular pressure (IOP) and osteonecrosis. While an every other day dosing schedule mitigates the occurrence of several steroid induced side effects, it only decreases the risk of cataract development without fully eliminating the risk, and does not affect the risk of osteoporosis/osteonecrosis at all.
A rapid response is usually noted once systemic glucocorticoids are initiated; however, prolonged therapy is often required to achieve clearance. With a long course comes many side effects and the elderly are particularly susceptible to these adverse effects. As such, the management of elderly patients mandates the lowest effective dose of corticosteroids with early initiation of adjuvant therapy. Examples of adjuvant therapies include immunosuppressive agents such as azathioprine and mycophenolate mofetil, and antibiotics such as dapsone. Such agents allow for a decreased dose of systemic corticosteroid needed to achieve disease control and their expedited tapering.
Prior to initiating any systemic immunosuppressive, a complete physical examination and age-appropriate malignancy screening should be performed. Baseline laboratory data may be helpful in selecting a steroid-sparing agent. Monitoring for potential adverse effects include a complete blood count (CBC) with differential, serum chemistry, liver function tests (LFT), fasting lipid profile, urinalysis, tuberculin skin test, hepatitis panel, glucose-6-phosphate dehydrogenase (G6PD) enzyme level (for dapsone), and thiopurine methyltransferase (TPMT) enzyme level (for azathioprine). Bone densitometry is indicated for those patients on a daily dose of prednisone 5mg or more for longer than 6 months. Blood pressure, blood glucose, and stool guaiac should also be monitored. Prophylaxis for Pneumocystis carinii pneumonia (PCP) should be considered in patients on long-term oral corticosteroids or other immunosuppressives with the exception of dapsone. However, recent data has shown that routine prophylaxis for PCP may not be necessary, recommending physicians who prescribe immunosuppressants for dermatologic indications to consider it on a case-by-case basis. Regardless, patients should be monitored closely for signs and symptoms of infection or malignancy in general, and if either occurs, appropriate treatment should be instituted early and aggressively.
Tetracycline along with nicotinamide has been used with some success in patients with mild pemphigus vulgaris, using tetracycline 2g daily along with nicotinamide 1500mg daily. This antibiotic regimen has a minimal side effect profile and is ideally suited for elderly patients. Side effects of tetracycline include gastrointestinal upset and phototoxicity; administration should be avoided in patients with renal impairment. The main adverse effects of nicotinamide include flushing and pruritus. Although this regimen is particularly useful in the elderly, it should be avoided in patients with renal impairment and in children less than 9 years old, as tetracyclines are associated with permanent tooth discoloration in the pediatric population.
Dapsone, historically used as a therapy for leprosy, is another antibiotic that can be used as adjuvant therapy for PV. Although some studies have shown no statistically significant difference in remission when dapsone was compared to placebo, dapsone has been documented to be extremely useful in controlling mild to moderate PV if introduced early in disease evolution. Dapsone is contraindicated in patients with low G6PD levels. In patients with normal levels, the degree of hemolytic anemia and associated symptoms may be avoided by gradually increasing the dose of dapsone. The drug can be started at 25 to 50mg per day and increased every third day by 25mg until 100mg is reached. Dapsone 100mg should be taken for one week before increasing to a target maintenance dose of 125 to 150mg daily. This gradual titration allows for the bone marrow to adapt to the hemolytic insult.
Other important adverse effects of dapsone include methemoglobinemia, agranulocytosis, and hypersensitivity syndrome. Patients should be counseled to expect a 1-2g drop in hemoglobin. Most patients can tolerate such a mild anemia, and this often does not necessitate discontinuation of the medication; however, decreases greater than 2g may require discontinuation. Baseline CBC including reticulocyte count should be obtained prior to initiation then frequently checked thereafter in order to monitor for this potential complication in addition to screen for agranulocytosis, which affects 1 in 400 patients and most often occurs after 8 to 12 weeks of therapy. Any significant rise in reticulocyte count (i.e. 5% higher than baseline) may warrant discontinuation of the drug. Dapsone hypersensitivity syndrome is an idiosyncratic reaction characterized by fever, generalized eruption, hepatitis, and peripheral eosinophilia, typically occurring eight weeks after drug initiation. When this occurs, discontinuation of the offending agent is required. Dapsone can also cause a distal motor peripheral neuropathy, which is usually reversible upon discontinuation. Therefore, patients should be monitored for hand and/or leg weakness or muscle atrophy throughout treatment duration.
Numerous immunosuppressive agents have been used as adjunctive therapy, particularly when there is severe disease or when disease extends beyond the oral cavity. Such agents include azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, and cyclosporine with monotherapy of the chosen immunosuppressive agent as the eventual goal. The use of azathioprine when combined with corticosteroids may result in gaining early control of disease and increased percentage of clinical remissions. Remission rates of 28-45% and mortality rates of 1.4-7% have been reported when azathioprine and systemic corticosteroids are used. Azathioprine has been used alone; however, its long latency of onset (up to 8 weeks) limits its use as initial monotherapy. The main adverse effects include hepatotoxicity, hypersensitivity syndrome, and neutropenia. Patients with low TPMT levels are at greater risk of neutropenia. Therefore dosing should be individualized based on the patient’s TPMT enzyme activity level. Individuals with high TPMT enzyme activity levels require higher doses to achieve clinical effect. Regular laboratory monitoring should include LFTs and CBC with differential. Azathioprine should not be prescribed in patients who take allopurinol unless unavoidable, since allopurinol interferes with the metabolism of azathioprine increasing plasma levels of 6-mercaptopurine, which may result in potentially fatal blood dyscrasias.
Mycophenolate mofetil is another adjuvant immunosuppressive used to treat PV. Similar to azathioprine, therapeutic effect takes approximately 6-8 weeks; however, mycophenolate mofetil has less hepatotoxicity and myelosuppression, but more gastrointestinal toxicity than azathioprine. Laboratory parameters including CBC with differential and LFTs should be checked regularly. Both azathioprine and mycophenolate mofetil can be used in conjunction with dapsone should the latter provide only partial control.
Cyclophosphamide is another adjunctive immunosuppressive agent used to treat pemphigus vulgaris. Its combination with systemic corticosteroids may result in gaining early control of disease and increased percentage of clinical remissions. Although cyclophosphamide is still typically used in combination with systemic corticosteroids, numerous case series have reported utilizing it as monotherapy with clinical effect in acute disease at doses of 50 to 200mg per day. Cyclophosphamide has a higher incidence of adverse effects including hemorrhagic cystitis, infertility, and bladder cancer when compared to azathioprine or mycophenolate mofetil. Regular laboratory monitoring includes CBC with differential and urianalysis. Given its potential risk of toxicity, it should only be used as short-term therapy with transition to an alternative adjuvant once disease activity is controlled. Furthermore, intravenous administration is available in those patients who cannot tolerate oral intake.
Methotrexate should be considered in patients where other adjuvant medications have failed or are contraindicated. The major adverse effect of methotrexate is total cumulative dose-dependent hepatotoxicity. Additional side effects include anemia, leukopenia, pulmonary toxicity, mucositis, and nausea. Doses ranging from 10-17.5mg once weekly are typically used to treat PV. The final adjunctive immunosuppressive cyclosporine is used concomitantly with prednisone in the treatment of pemphigus vulgaris. Known adverse effects include hypertension, nephrotoxicity, hepatitis, and neurologic changes. With such a toxicity profile, cyclosporine should be not considered first-line adjuvant therapy, but may be used to achieve rapid initial control.
Two final medications used to treat pemphigus vulgaris—one more recently debuted, the other more historic—are rituximab and gold. The former has activity against tumor necrosis factor alpha (TNF-α), and recently emerged as a choice for refractory cases to more standard immunosuppressive therapy because of its ability to target plasma cell precursors responsible for antibody production. Most patients respond within 3 months after starting rituximab; however, delayed response after a year of treatment has been reported. Its use is limited by cost, infusion route of delivery, and potential for serious immunosuppression and infection. Other biologics such as etanercept and infliximab have been investigated in treating PV; however, results are variable. Gold has been used to treat mild to moderate cases of PV as monotherapy or with oral glucocorticoids. Two early studies reported complete remission in 15-44% in a total of 44 PV patients; however, it was considered ineffective in 15-28% of patients while 17-35% discontinued the due to side effects. Gold is rarely used today because of its delayed onset of action, side effect profile, and relative ineffectiveness compared to other treatments available.
Immunomodulatory procedures such as intravenous immunoglobulin (IVIg), plasmapheresis and extracorporeal photopheresis have all been employed in the management of pemphigus vulgaris. High dose IVIg (2g/kg per cycle) may be necessary in patients with rapidly progressive, extensive, or treatment resistant PV. IVIg has a very rapid onset of action, and has been used with oral corticosteroids and an immunosuppressant drug in patients with refractory PV; however, consensus on its efficacy remains controversial, as well as duration of treatment. Plasmapheresis plays a limited role in the management of PV, but can be considered in difficult cases. Plasmapheresis is useful for quickly reducing very high titers of autoantibodies, and should be considered in severe presentations if unresponsive to a combination of immunosuppressants and corticosteroids. Extracorporeal photopheresis has been used in patients with PV; however, clinical efficacy is variable. One final medication with cytokine-modulating effects recently reported in treating PV is thalidomide. The report showed it to be a very effective treatment option deserving further evaluation. The recommendation was to consider the use of this drug for patients in whom standard therapy, IVIg, and rituximab have all failed. Table 8.1 outlines therapeutic options in the treatment of most autoimmune blistering diseases.
Pemphigus vegetans, a rare clinical variant of pemphigus vulgaris affecting 1-2% of patients, is thought to represent a reactive pattern of the skin to the autoimmune insult of PV. Pemphigus vegetans is characterized by the occurrence of hypertrophic, papillomatous, or verrucous vegetating skin lesions predominately involving the intertriginous areas. In general, flaccid blisters become erosions with subsequent formation of fungating vegetative plaques.
Two clinical subtypes of pemphigus vegetans are recognized: the Neumann type and the Hallopeau type. The former is more severe with longstanding and refractory erosions that transform into vegetating lesions, while the latter is a milder presentation characterized by the initial appearance of pustules and rapid evolution to verrucous vegetative plaques with persistent peripheral pustules. Diagnosis may be difficult in patients with chronic vegetations, but the DIF staining is identical to that seen in classic PV. As in PV, systemic corticosteroids are the principal treatment for pemphigus vegetans. Patients with the Neumann subtype have a similar disease course to PV, mandating higher steroid doses with multiple remissions and relapses, while patients with the Hallopeau subtype have a benign disease course, only needing low doses of steroids with longer remissions. As such, morbidity and mortality is similar to PV for the Neumann subtype.
Like pemphigus vulgaris, pemphigus foliaceus (PF) is one of the originally characterized classic forms of pemphigus. PF is generally a more benign variant; however, localized lesions tend to persist for months to years carrying a significant amount of morbidity for some patients. Although PF is not often associated with considerable mortality, the disease can progress to erythroderma (see Chapter 008) representing a true dermatological emergency. These patients require prompt hospitalization to prevent serious and sometimes fatal complications from high output cardiac failure and metabolic instability.
Sporadic PF is a rare disease accounting for 20-30% of pemphigus cases. Its incidence in the United States and Europe is estimated at less than 1 case per million inhabitants per year. The prevalence of PF is approximately equal between men and women affecting all races and ethnicities with an average age of onset between 40-60 years old. The epidemiologic statistics exhibit considerable variation when examining the endemic forms of PF as discussed later. The exact cause of sporadic PF remains unknown; however, extensive UV exposure, burns, and various drugs have all been implicated in its development. Penicillamine and captopril are the two medications in particular that are associated with PF, and in patients receiving penicillamine, PF is seen more commonly than PV with a ratio of approximately 4:1. Similar to PV, one dietary factor has also been reported in giving rise to PF seen in a patient taking herbal supplements with phycocyanin. An overlap syndrome exists that exhibits characteristics of both PF and systemic lupus erythematosus called Senear-Usher Syndrome, or pemphigus erythematosus. The name was used to describe patients with overlapping immunologic features of both diseases (IgG and C3 deposition and circulating antinuclear antibodies); however, only a few patients have been reported to actually have the two diseases concurrently.
In pemphigus foliaceus, blister formation is associated with IgG antibodies against desmoglein 1 only, which is essential to keratinocyte cohesion only in the most superficial layer of the epidermis DIF is similar to that in PV, but a stronger staining has been described in the upper epidermal portion. IIF shows mainly IgG4 antibodies best detected using guinea pig esophagus. Anti-desmoglein 1 antibodies are frequently detected with ELISA assays on serum of PF patients in more than 90% of cases. Desmoglein 1 values parallel the course of the disease. Antibodies directed against desmoglein 3 are not detected as it has been clearly demonstrated that autoantibody reactivity is restricted to desmoglein 1 in PF.
Clinically, the primary lesions seen in pemphigus foliaceus are flaccid superficial vesicles and bullae confined to the skin. Such lesions may not necessarily be seen at time of presentation since they are both transient and fragile. Therefore, secondary lesions are more often seen including shallow erosions with extensive crusting. Lesions are typically well demarcated and have a seborrheic distribution favoring the face, scalp, upper trunk, and back.
Therapy for pemphigus foliaceus is usually less aggressive than that of PV because of lower morbidity and mortality rates. In general, the treatment is similar to PV when patients with PF present with active and widespread disease. Such extensive cases may require adjuvant immunosuppresants such as systemic corticosteroids, azathioprine, cyclophosphamide, or mycophenolate mofetil. In some patients with PF, disease activity may remain localized for many years and topical high potency corticosteroids may provide sufficient control. Dapsone might be considered when neutrophils are dominant histologically.
Fogo selvagem (FS) is an endemic subtype of pemphigus foliaceus. Endemic PF differs from the sporadic form of the disease in its geographic distribution, high familial incidence, and younger age of onset. Patients are clinically, histologically, and immunopathologically similar to patients with sporadic PF; however, a higher incidence of more severe, generalized exfoliative dermatitis is related to a higher morbidity and mortality seen in FS.
Fogo selvagem occurs with a high frequency in Central and Southwestern Brazil where as many as 50 cases per million per year are seen. Some endemic regions of Brazil exhibit a prevalence equal to 3% of the population, where the ratio of FS to PV is 17:1. FS affects a larger number of children and young adults without sex predilection as symptoms usually begin during the second or third decade of life. Another focus of endemic PF exists in the northern part of Columbia. The prevalence of Columbian PF is close to 5% and greater than 95% of those affected are men. A third focus of endemic PF has also been described in Tunisia. There, the overall incidence is 6 to 7 cases per million per year; however, the incidence dramatically increases up to 20 cases per million per year in some areas in south Tunisia, particularly affecting young adult women from 25 to 34 years old as evidenced by a female to male ratio of 4:1.
The exact cause of fogo selvagem is unknown. FS frequently occurs in genetically related family members, and more than 50% of normal individuals in certain areas of Brazil have antidesmoglein 1 IgG autoantibodies. In addition to genetic propensity, FS is thought to be triggered by the bite of an insect, where antibodies produced against this unidentified antigen may cross-react with desmoglein 1 in genetically susceptible individuals, leading to the development of FS.More recent research has focused on the study of a protein transmitted from the saliva of Simulium nigrimanum, a type of black fly. Dietary factors have also been implicated as increased amounts of tannins dissolved in the water systems directly serving Amazonian natives could explain the occurrence of FS in Amazonian Brazil.
The target antigen in fogo selvagem is desmoglein 1 with similar DIF and IIF staining patterns as seen in PF. Clinically, patients with FS exhibit the same characteristics as patients with PF. Some patients with chronic disease may develop verrucous plaques on the trunk and extremities, which have also been described in patients with Columbian endemic pemphigus. Hyperkeratosis on the soles and palms is also frequently observed. Therapeutics are similar to those used in PF.
Of the entire pemphigus family, paraneoplastic pemphigus (PNP) is the most severe. PNP carries significant morbidity and mortality, partially due to development in the setting of malignancy and also the associated often extensive mucosal involvement. When PNP is associated with malignancy, mortality is estimated at 93% usually from sepsis, bronchiolitis obliterans, or progression of the underlying malignancy.
Epidemiological data on the prevalence and incidence of PNP is scarce. One review reported approximately 150 cases in the literature ten years ago. The age range for paraneoplastic pemphigus is from 7 to 83 years, although the majority of patients are between the ages of 45 and 70 years. The mean age at onset is 60 years without predilection of sex or race. PNP occurs in the setting of malignancy including, in decreasing order of frequency, non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, thymoma, Waldenstrom macroglobulinemia, and spindle-cell sarcomas.
PNP patients display autoantibodies to desmoglein 1 and 3, as well as desmosomal proteins of the plakin family including desmoplakin I and II, envoplakin, periplakin, plectin, BP antigen 230, and a 170-kDa protein that has not been further identified. DIF reveals IgG, C3, or both in an intercellular pattern like PV, but in addition, linear/granular IgG or C3 may be present at the basement membrane zone. Results of IIF are similar to PV but autoantibodies may also demonstrate binding to simple or transitional epithelium substrates like rodent bladder, which is considered unique and diagnostic of PNP.
Severe involvement of multiple mucous membranes is the major clinical feature and hallmark of this disease. The most constant clinical feature is severe and intractable stomatitis consisting of erosions and ulcerations that affects all surfaces of the oropharynx, characteristically extending to the vermilion lip. Mucosal involvement may also include the conjunctiva, genitalia, or tracheobronchial tree. Such extensive mucosal involvement is a considerable source of morbidity in PNP patients as the conjunctival fornices may become scarred and obliterated leading to synblepharon, while esophageal ulceration may lead to hypoalimentation and malnourishment. The cutaneous findings are by definition polymorphous and may present as erythematous macules, flaccid blisters and erosions resembling PV, tense blisters resembling bullous pemphigoid, erythema multiforme, or lichenoid dermatitis.
Treatment is aimed at the underlying malignancy, but the course of PNP does not correlate with the course of the underlying neoplasm. Patients with benign tumors such as a thymoma or localized Castleman’s disease should have them surgically excised, as the majority of these patients will significantly improve. There is no consensus on a standard effective therapeutic regimen for patients with malignant tumors. Cutaneous lesions respond more rapidly to therapy in contrast to the stomatitis, which is generally refractory to most treatment measures. Aggressive combinations of immunosuppressants including systemic corticosteroids, rituximab, and others have been used but are frequently unsuccessful. Yet another source of morbidity in these patients with PNP is the susceptibility to infection caused by the loss of skin integrity, exacerbated by the potent immunosuppressants used to treat the condition.
EPIDERMOLYSIS BULLOSA SIMPLEX
Epidermolysis bullosa simplex is one of three major forms of inherited epidermolysis bullosa (EB), which is the prototypic mechanobullous disease, characterized by the development of blisters after trivial trauma to the skin. Most epidemiologic data is derived from the work of the National EB Registry stating that 50 EB cases occur per million live births and approximately 92% are classified as EB simplex. EB simplex is mostly transmitted in an autosomal dominant fashion and appears to be the result of mutations within the gene for either keratin 5 (K5) or keratin 14 (K14), which are present primarily within the basal layer of the epidermis. Transmission electron microscopy (TEM) distinguishes among the three major EB types by the identification of the ultrastructural level of cutaneous blister formation. TEM can also be used to quantitatively and qualitatively assess specific structures such as basilar tonofilaments, hemidesmosomes, subbasal dense plates, anchoring filaments and anchoring fibrils.
EB simplex is characterized by mechanically fragile skin, tense fluid-filled blisters, erosions and crusts with subsequent atrophic scarring. These features are seen beginning at birth or soon after. The more severe subtype of EB simplex known as EB simplex herpetiformis, or Dowling-Meara, is characterized by grouped blisters often in an arcuate or polycyclic array, and also associated with the most significant mucosal membrane involvement and increased mortality. Morbidity and mortality of EB simplex relates to the consequences of repeated damage, ulceration, and poor healing of the skin. Malnutrition and growth stunting is consistently seen in patients with EB simplex. This may be due to oral blistering and ulcerations, digestion and absorption problems, or loss of blood and protein through open skin blisters. Although more common over a decade ago, bacterial sepsis and subsequent death is now relatively rare; however, it can still occur in the EB simplex Dowling-Meara subtype, and hypermetabolism resulting in increased heat loss and protein turnover is especially common in the setting of skin infections.
There are no FDA approved therapies for any form of inherited EB, but two clinical trials involving molecular therapy are currently underway and specific treatment may become a reality for at least some types or subtypes of EB in the near future. One clinical trial is investigating bone marrow transplantation and immunosuppression to deliver corrective skin cells in the patient, while the other clinical trial is examining retroviral mediated type VII collagen gene transfer. For now, daily management revolves around the prevention of both mechanical trauma through the use of padded bandages and loose-fitting garments, in addition to the prevention of infection via mild, broad-spectrum topical antibiotic ointments or creams. Experience in a few patients suggests that systemic tetracycline might be of clinical benefit in EB simplex. Most of the extracutaneous complications of EB can be surgically or medically managed. In patients with significant malnutrition, aggressive nutritional supplementation facilitated by placement of a gastrostomy tube can be performed when necessary. Genetic counseling should be considered as genetic information from mutation analyses on epidermolysis bullosa candidate genes provides an immediate benefit to families of patients with the disease. Prenatal diagnosis of epidermolysis bullosa in affected families is a genetic-based protocol, providing that the patient identified as the original proband has had identification of the defective gene, and chorionic villus sampling as early as 8 to 10 weeks or amniocentesis in the second trimester are both used to aid in diagnosis.
SUBEPIDERMAL BLISTERING DISEASES
Subepidermal blistering diseases often requiring emergent attention include bullous pemphigoid, gestational pemphigoid, cicatricial pemphigoid, linear IgA bullous dermatosis, and epidermolysis bullosa acquisita in addition to two heritable disorders known as junctional epidermolysis bullosa and epidermolysis bullosa dystrophica. All the acquired disorders are characterized by circulating and tissue-bound autoantibodies against various components of the dermo-epidermal anchoring complex (hemidesmosome), whereas the inherited disorders result from various defects in these hemidesmosomal proteins.
Bullous pemphigoid (BP) is the most commonly encountered autoimmune, subepidermal blistering disease of the skin, most commonly affecting the elderly. Elderly individuals are more likely to have comorbid conditions, and the presence of such conditions complicates the selection of and effect of therapy and may also dramatically influence both prognosis and outcome. Elderly patients also frequently have suboptimal nutritional states that can adversely affect prognosis and further complicate care. The morbidity and mortality in BP is also influenced by its chronicity with periodic remissions and exacerbations with a profound impact on quality of life. Among studies of patients with BP published in the past two decades, one-year mortality rates ranged from 15-41%
Previously published case series have documented an age of onset range from 68 to 82 years. The annual incidence of BP is estimated to be at least 6-7 new cases per million per year with a rapid increase after the age of 60 years, and expected to rise given the advancing age of the population. The relative risk for patients over 90 years of age appears to be about 300-fold higher than for those 60 years of age or younger with an apparent predominance in men. Certain HLA class II alleles are more prevalent in patients with BP than in the general population including DQB1 in Caucasians and DRB1 in Japanese. Most cases of BP occur sporadically without any obvious precipitating factors; however, several reports have implicated various triggers such as UV light, radiation therapy, percutaneous endoscopic gastrostomy, thermal burn, amputation stump, and adhesive dressings. BP has also been reported to develop in associated with other autoimmune diseases like diabetes mellitus and pernicious anemia, chronic inflammatory skin diseases such as lichen planus and psoriasis, and various malignancies. Despite the various case reports of BP associated with renal cell carcinoma, gallbladder malignancy, and colon and breast cancers, large population studies have reported conflicting evidence. Therefore, the relationship between BP and malignancy is still a matter of debate. Medications associated with bullous pemphigoid include furosemide, ibuprofen and other NSAIDs, captopril, penicillamine, and antibiotics.
The target antigens in BP are components of the hemidesmosome in cutaneous basal cells. Most BP patients have bound and circulating IgG antibodies directed towards the extracellular noncollagenous domain of collagen type 17, a transmembrane protein in basal cells also known as BP180 (BPAg2). Patients with BP also exhibit autoreactivity to a cytoplasmic plakin family protein known as BP230 (BPAg1), which is also a structural part of the hemidesmosome. DIF studies are generally considered more sensitive than IIF because circulating antibodies may not be detectable in a small but significant portion of patients; however, if the DIF does not display the characteristic pattern (i.e. deposition of IgG and/or C3 at the basement membrane zone), serum for IIF on salt-split skin and/or BP180 ELISA may be necessary to differentiate BP from the inflammatory variant of epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, and mucus membrane pemphigoid (MMP).
The clinical presentation of BP is highly variable. Patients may seek medical attention during the initial nonbullous phase, which is often a simple complaint of pruritus or urticarial patches, plaques and erythema with no evidence of bullae. When blisters eventually develop, they are classically 1-4cm in size, tense, bilateral, and symmetric with predilection for the flexural proximal extremities and trunk. Pruritus is common and mucosal involvement can occur in a minority of patients and often limited to the oral cavity. Several variants of BP exist, and many carry unique morbidity and mortality characteristics. For example, dyshidrosiform pemphigoid—a localized variant of BP often presenting with recurrent, painful vesicles and bullae of the palms and/or soles—can lead to significant functional impairment, whereas erythrodermic pemphigoid tends to induce a high output cardiac failure placing patients at risk for sepsis and subsequent death. Interestingly, the overall trend in mortality over a 24-year period was found to increase in pemphigoid but decrease in pemphigus, while mortality in the black population was significantly higher for every bullous disorder.
Systemic corticosteroids are the most effective therapy for BP, and prednisone given at doses ranging from 0.5-0.75 mg/kg/day is generally sufficient for disease control. More recent reports have been published in regards to the efficacy of topical corticosteroids in the treatment of BP; however, it is still unclear whether topical steroids are unequivocally better than systemic regimens. Additional therapies for BP with documented efficacy include azathioprine, methotrexate, and tetracycline with nicotinamide. In treatment resistant cases, IVIg, plasma exchange, or rituximab are all potential options, discussed more extensively in the pemphigus vulgaris section.
Pemphigoid gestationis is one of the dermatoses of pregnancy that places both mother and fetus at risk, and emergent diagnosis and treatment is paramount in order to prevent any significant morbidity to either. It is intensely pruritic and generally develops in the third trimester or the immediate postpartum period. Case reports have documented an association with pemphigoid gestationis and subsequent development of choriocarcinoma. The mother is also at increased risk for enduring the same eruption with subsequent pregnancies. Fetal morbidity and mortality includes low birth weight for gestational age and prematurity. In addition to the possibility of fetal adrenal insufficiency and transient neonatal pemphigoid exist from transplacental antibody transfer exist, although much less common.
The incidence of pemphigoid gestationis is estimated to be 1 in 50,000 pregnancies in North America. Only 14% of cases develop in the postpartum period. An increased risk for the development of this disease has been delineated in patients with HLA-DR3 and HLA-DR4 alleles. Those patients with this same haplotype also have a higher relative prevalence of other autoimmune diseases including Hashimoto thyroiditis, Graves disease, and pernicious anemia. Pemphigoid gestationis appears to be caused by an anti-basement membrane zone (BMZ) serum factor that induces C3 deposition along the dermal-epidermal junction. The majority of patients also have antibodies to BP180 (as seen in BP patients) of the IgG1 subclass. The gold standard in diagnosing pemphigoid gestationis is DIF on perilesional skin, which shows a bright linear deposition of C3 along the BMZ in 100% of cases, an immunopathologic hallmark. IIF shows circulating IgG antibodies in 30-100% of cases, and in salt-split skin, staining remains with the epidermal fragment as seen in patients with BP.
The initial clinical findings of pemphigoid gestationis are characterized by the presence of severe pruritus and erythematous urticarial papules, which coalesce into plaques. The typical localization of the lesions is on the abdomen and exclusively within or proximate to the umbilicus. In atypical cases, the lesions tend to cluster over the limbs, palms, or soles. Lesions spare abdominal striae unlike the lesions in pruritic urticarial papules and plaques of pregnancy (PUPPP) that have a predilection of involving abdominal striae. As lesions progress over the course of days to weeks, tense blisters develop, and a generalized pemphigoid pattern of eruption becomes evident. The bullae are similar to those found in BP—tense with serous fluid and often leaving widespread erosions. The entire skin surface can be involved, but the face, palms, soles, and mucous membranes are usually spared. Systemic corticosteroids are the cornerstone of therapy and most patients respond to prednisone 0.5 mg/kg/day. Maintenance therapy is generally held at a lower dose and may not even be required throughout gestation depending on response. Interestingly, many patients will experience spontaneous disease regression during the third trimester, only to experience a flare during childbirth.
Many pregnant women become concerned with the risks of systemic steroids on fetal well-being, and these apprehensions should be appropriately addressed. There is an increased inclination to develop fetal risks such as small for gestational age and prematurity suggesting a low-grade placental insufficiency; however, it has recently been shown that these risks seem to be more associated with antibodies binding to the placenta rather than the effect of systemic steroids. The other potential risk to consider is adrenal insufficiency, especially in those women treated with systemic steroids over longer periods of time; however, the maternal-fetal gradient of prednisone is only 10:1 and fetal adrenal suppression is only a rare consequence.
MUCOUS MEMBRANE (CICATRICIAL) PEMPHIGOID
Mucous membrane pemphigoid (MMP) is a chronic inflammatory subepidermal blistering disease. MMP is characterized by the presence of antibodies targeting subepidermal BMZ structural components of mucosal surfaces. The morbidity and mortality for this disease are significant, and serious sequelae can develop including scarring and fibrosis of the involved mucous membranes. The disease course is often slow and progressive interrupted with periods of explosive inflammatory activity.
MMP is rare but most often affects elderly individuals with a 2:1 female preponderance aged 60 to 80 years, and an average age ranging from 62 to 66 years. However, MMP has also been reported in children. The incidence of MMP is estimated to be between 1 in 12,000 and 1 in 20,000 in the general population. Although no geographic or racial predilection has been described, several studies have demonstrated an increased risk in patients with an HLA-DQw7 haplotype. No specific diseases or predisposing factors have been noted in association with MMP, with the exception of colon cancer in patients with antilaminin 5 (epiligrin) MMP.
Laboratory evidence suggests that the autoantibodies in MMP can target multiple different structural components of the extracellular portions of the hemidesmosomal adhesion complex in the skin and mucosal surfaces. The various target antigens can include BP180, BP230, laminin 5, laminin 6, and integrin alpha-6/beta-4 subunit. Patients with antibodies against the integrin subunits predominantly exhibit ocular disease. Patients with antibodies against laminin 5 have no specific phenotype, and whereas those with BP180 autoantibodies can exhibit cutaneous involvement.
Similar to BP, immunofluorescence studies are the gold standard for diagnosis. Biopsy for DIF is best obtained from perilesional uninvolved mucosa such as the lower labial mucosa which is easily accessible. In general, MMP is characterized by the linear deposition of IgG, IgA, and/or C3 along the epidermal BMZ in mucosal and/or cutaneous biopsy specimens. IIF is positive in approximately 20-30% of cases in contrast to the much higher detection rate seen in BP. Given the lower detection rate with IIF on human split skin, Western blotting, immunoprecipitation, and ELISA using various cell-derived and recombinant proteins are pivotal diagnostic tools for MMP. Despite a low detection rate, laminin 5 detected on the dermal side of salt split skin differentiates it from all other pemphigoids.
The diagnosis of MMP should be entertained in patients with erosive or blistering mucosal lesions, especially if evidence of scarring is present. Erythema multiforme, erosive lichen planus, and PV should be considered and can be differentiated by histology and immunofluorescence studies. BP, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis should also be included in the differential diagnosis.
The most common sites of MMP involvement are the oral mucosa and conjunctival mucosa, but the nasopharynx, esophagus, larynx, and anogenital mucosa can also be affected. Approximately 25% of patients will display cutaneous involvement, typically scalp, but mucosal disease predominates in true cases of MMP. Any part of the mouth can be affected including the attached gingiva, hard palate, and buccal mucosa. A common clinical presentation is that of a painful, erosive gingivitis, and intact blisters are usually not apparent. Symptoms and clinical findings in early ocular MMP are often nonspecific, and patients may complain of burning, pain, or foreign body sensation.
MMP carries significant morbidity and mortality often resulting from severe consequences arising from untreated disease. Chronic and progressive ocular inflammation can lead to scar formation, ultimately resulting in blindness. Laryngeal webs may develop causing sore throat, hoarseness, and possible loss of speech. Supraglottic stenosis secondary to erosions, scar formation, and edema may necessitate a tracheostomy as the airway becomes progressively compromised. Esophageal strictures can result in dysphagia, odynophagia, hypoalimentation, malnourishment, and subsequent weight loss. And finally, involvement of the anogenital mucosa may lead to urinary stricture and sexual dysfunction.
Several treatment modalities exist, and most patients with extensive disease will require long-term therapy. Excellent oral and ocular care should be emphasized in patients diagnosed with MMP. Therefore, patient care should coordinate the services of both an ophthalmologist and dentist (see PV for more information on oral care). In regards to ocular care, frequent lubrication with artificial tears to prevent dryness is recommended, and topical cyclosporine can be considered for extreme dryness although burning may limit compliance. Placement of lacrimal punctal plugs is recommended if patients do not already have occluded puncta secondary to scarring. It is also important to clean debris and exudate that accumulates in order to prevent secondary infection. Cleaning can also be achieved with artificial tears, but buffered preserved saline solutions are also available for patients that need an extra cleanse.
For MMP localized to the oral cavity with or without cutaneous involvement, the first line therapy has been topical corticosteroids such as dexamethasone swish. Other vehicles have been used such as corticosteroid gels, which are more easily applied and better tolerated within the oral cavity. There are few recognized adverse effects associated with steroid use in the oral cavity including oral candidiasis and herpes simplex virus reactivation. Topical corticosteroids should not be used alone and are not effective in controlling disease progression in ocular MMP. Although corticosteroid injections have been used for ocular MMP, it only achieves short-term results and carries a risk of cataract formation. Subconjunctival injections should only be performed by an ophthalmologist, but are rarely used in clinical practice.
Dapsone can be used as first-line therapy in localized MMP or slowly progressing, extensive disease as it can take 10-12 weeks before producing benefit. Systemic corticosteroids are the first-line therapy for treatment of extensive MMP, rapidly progressive MMP, or in patients with ocular, laryngeal, esophageal, severe anogenital or severe gingival involvement causing loosening of teeth. However, systemic corticosteroids alone are frequently inadequate for disease control and adjuvant immunosuppressants are often required. Azathioprine is the first choice of adjuvant therapy in MMP, provided the disease is not rapidly progressive and threatening vision. Mycophenolate mofetil has also demonstrated efficacy as an adjuvant therapy; however, cyclophosphamide is used in aggressive MMP, as it achieves efficacy sooner than either azathioprine or mycophenolate mofetil.
Other treatment modalities include the use of IVIg, which has a very rapid onset of action and found to be especially helpful in patients with progressive ocular MMP suffering from active deterioration of vision There has been reported success using etanercept and infliximab in the management of MMP. Rituximab has been reported to be successful in three cases of recalcitrant MMP. A single case of thalidomide use in refractory MMP has been reported, which may be considered in patients that are not responding to conventional therapies. Subconjunctival mitomycin C injections have been used by ophthalmologists in the treatment of ocular MMP and reserved as an option of last resort. Despite the numerous treatment options available, decisions must be heavily weighed against the potential adverse effects of therapy, and particularly in elderly patients with multiple comorbidities.
LINEAR IGA BULLOUS DERMATOSIS
Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disease with a heterogenous clinical presentation often idiopathic or drug induced affecting both adults and children. The morbidity and mortality of this disease largely rests on whether mucous membranes as these lesions will tend to heal with scarring. Desquamative gingivitis may secondarily damage teeth, while ocular involvement can potentially lead to blindness as seen in MMP. Adults often deal with higher morbidity rates as the disease course is prolonged as compared to children.
The true incidence of LABD is unknown, but the incidence in southern England has been estimated to be 1 in 250,000 per year. Incidence in the United States has not been reported. LABD can occur at any age, but there are two peaks of onset: an average age of onset at 60 years in adults, and an average age of 4.5 years in children. Many drugs have been reported in association with LABD, but nearly half the cases are due to vancomycin. Other important inducers of LABD include captopril, penicillins, cephalosporins, and non-steroidal anti-inflammatory agents. Another factor affecting the morbidity and mortality of LABD includes the documented association with malignancy seen in B-cell lymphoma, chronic lymphocytic leukemia, and carcinoma of the bladder, thyroid and esophagus.
Linear IgA disease antigen-1 (LAD-1), the 120-kDa cell-derived soluble ectodomain of BP180 is the major target antigen of IgA autoantibodies in patients with linear IgA disease. BP230 is an additional target antigen in the disease. The diagnosis of LABD is based on histology, which invariably shows a subepidermal blister with a superficial dermal infiltrate of neutrophils. DIF is confirmatory with homogenous, linear IgA deposits at the BMZ. Rarely, weak deposits of IgG and C3 at the BMZ may also be present. IIF can be either negative or detect low levels of IgA BMZ autoantibodies that would react with the epidermal, dermal, or both sides of the blister when tested on salt-split skin substrate.
As previously mentioned, LABD can vary in its clinical presentation; however, patients classically present with symmetric, grouped, annular vesicles and bullae on the trunk and extensors that are usually pruritic and often excoriated. Annular arrangement at the periphery showing a tendency to heal in the center is a characteristic feature of LABD known as the “cluster of jewels” sign. Atypical presentations of LABD have been described including forms that resemble erythema multiforme, toxic epidermal necrolysis, and a morbilliform eruption. Mucosal involvement can occur, but is less commonly seen in drug-induced LABD, which appears within 7-14 days of starting the offending agent.
The majority of LABD cases will respond to either oral dapsone or sulfapyridine therapy, and most patients have a clinical response within 48-72 hours. The average dose of dapsone needed for disease control is 100mg daily, however, doses as high as 300mg may be required. On occasion, the addition of oral prednisone in doses up to 40mg daily for complete control of the disease may be required. The treatment for drug induced LABD involves discontinuation of the suspected causative agent, and improvement is usually evident within 3 weeks.
EPIDERMOLYSIS BULLOSA ACQUISITA
Epidermolysis bullosa acquisita (EBA) is an extremely rare, acquired subepidermal blistering disorder, associated with significant morbidity resulting from involvement of various skin and mucosal surfaces including similar irreversible complications as seen in MMP such as blindness and esophageal strictures. Tracheal involvement and upper airway obstruction requiring tracheostomy has been described. Indeed, more aggressive cases of EBA are often difficult to control and associated with a significant mortality rate. EBA is a chronic disease that is difficult to treat and for which there is no cure.
The exact incidence and prevalence of EBA is unknown, but it seems rare overall. Few available studies showed an incidence of 0.22 cases per million per year in Germany, 0.26 per million per year in France, 0.23 per million per year in Kuwait, and a slightly higher incidence of 0.5 per million per year in Singapore. EBA may occur in patients of any age with an average age at onset of 40 years, and unlike BP does not exhibit a predilection for the elderly. The disease does seem to be slightly more common in women and black patients. The cause is unknown, but genetic predisposition is likely given its association with specific haplotypes HLA-DR2 and HLA-DRB1. A number of disorders have been anecdotally reported with EBA including systemic lupus erythematosus, amyloidosis, autoimmune thyroiditis, diabetes mellitus, and multiple endocrinopathy syndromes. The most frequent association is with inflammatory bowel disease.
EBA is characterized by IgG autoantibodies targeting type VII collagen, which is unique to stratified squamous epithelium and is the primary component of the anchoring fibril in the BMZ connecting the lamina densa to the papillary dermis of skin and mucosa. Two clinical types of EBA exist—the classic form and inflammatory form. The latter contains varying degrees of inflammation with lymphocytes, neutrophils, and eosinophils distinguishing it from the former on histology. Inflammatory EBA is a great mimicker of BP; thus, the distinction between the two can only be made with immunofluorescence studies and clinical course. DIF microscopy reveals linear deposits of IgG along the BMZ, with variable presence of linear C3, IgA, and IgM. The intensity of IgG is generally greater than the other substrates. IIF can be useful in differentiating EBA from BP since circulating IgG antibodies along the dermal side of salt-split skin can only be detected in 10-30% of cases of EBA. Furthermore, a more sensitive ELISA for the detection of antibodies against type VII collagen is also available.
The differential diagnosis of classic EBA includes variants of porphyria, pseudoporphyria, and hereditary forms of epidermolysis bullosa, while inflammatory EBA must be distinguished from BP, LABD, MMP, bullous drug eruptions, and bullous lupus. Disruption of type VII collagen function results in the clinical manifestations seen with this disease, and also found disrupted in bullous lupus although the latter often presents with a known history or other signs or symptoms of systemic lupus erythematosus. Patients with classic EBA present with blisters, arising in areas of the skin where frequent and minor trauma can occur on noninflammed skin including the dorsum of the hands, knuckles, elbows, knees, sacral area, and feet. Healing results in scarring and milia formation. Approximately half of all patients present with inflammatory EBA, which constitutes a vesiculobullous eruption most prominent over the trunk and flexural skin. As opposed to classic EBA, skin fragility is not a chara