2014 November Dermatology Look-Alikes
2014 November Dermatology Look-Alikes
A 94-year-old woman presents with a 10-day history of itchy, tense blisters that break open and leave a hemorrhagic crust. She has no other symptoms and was taking lisinopril, hydrochlorothiazide, and simvastatin. Physical exam revealed scattered, tense bullae over normal and erythematous skin in symmetrical distribution on the lower back as patchy coalescing erosions and on the inguinal region; there were discrete ulcers with hemorrhagic crusts on the lower face, chest, and proximal upper and lower extremities. There was no oral mucosal involvement.
A 31-year-old woman at 30 weeks’ gestation presents with itchy, tense blisters that have spread from the abdomen toward the distal extremities for the last 2 to 3 weeks. She was taking multivitamins but no medications, and she has no medical history. Physical exam revealed erythematous periumbilical annular plaques with tense bullae containing serous fluid. Plaques with central erosion were scattered more peripherally over the abdomen, arms, and legs. Pink plaques with yellow vesicles were present over the volar wrists and dorsal feet bilaterally.
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Bullous pemphigoid (BP) is the most common autoimmune disease that results in subepidermal blistering. This condition typically presents with generalized itchy eruptions with blisters and can be associated with significant morbidity. In the early stages, the blisters can have quite a polymorphic clinical appearance in the absence of vesicles and bullae.
Considered a disease of the elderly, BP usually does not develop until after age 60 years.1,2 Each year, approximately 6 to 13 new diagnoses of BP are made per 1 million people.1 Interestingly, patients older than age 90 years are at an approximately 300-fold greater risk for developing BP than are patients younger than age 60 years.1 There also appears to be a higher predominance of the disease in men than in women.
BP is an autoimmune disease associated with both a humoral and cellular response against 2 antigens in the skin: BP antigen 180 (BP180) and BP antigen 230 (BP230). Both of these antigens are found in the hemidesmosomes, which are adhesion complexes that function in epithelial-stromal adhesion at the subepidermal level.1,2
Most patients with BP develop circulating immunoglobulin G (IgG) antibodies against BP180 on the noncollagenous NC16A domain, which can be detected in the serum in 70% of these individuals. They also exhibit autoreactivity to intracellular BP230 at the C-terminal region.1 The autoantibodies stimulate a T-cell response and production of more autoantibodies by B cells.
It is thought that T helper cell type 2 (Th2) cytokines are important in BP pathophysiology. Binding of the autoantibodies results in subepidermal blister formation and a cascade of events including complement activation and inflammatory cell recruitment predominantly of neutrophils and eosinophils. Chemokines and proteases degrade the extracellular matrix proteins. Mast cells and eosinophils release proteases and proinflammatory mediators that produce more tissue damage and inflammation, further weakening the dermal-epidermal adhesion.1
Since patients with BP can initially present with nonspecific symptoms such as itching, urticarial-like or eczematous lesions, or excoriations, BP should be on the differential for any elderly patient who complains of itchiness with or without primary skin findings.1,2 In our patient, the bullous phase of BP was a much more straightforward diagnosis.
Classically, blisters in BP are tense lesions that are approximately 1 to 4 mm in diameter and filled with clear fluid. These bullae can persist for several days and may even become tinged with blood, but then subsequently leave eroded and crusted areas.
Often, lesions present in a symmetrical distribution and have a penchant for flexural surfaces of extremities and the lower trunk. They may appear more like vegetating plaques in intertriginous areas. In these patients, always examine all mucosal areas for lesions.
The oral cavity is involved in 10% to 30% of patients, and in rare cases, the eyes, nose, pharynx, esophagus, and anogenital region can be involved. A complete blood count with differential may show eosinophilia, which is present in about 50% of patients with BP.1
Work-up of suspected BP should always involve a review of the patient’s systemic medications. Numerous drugs are implicated as inducing BP. These include diuretics (e.g., furosemide and bumetanide), analgesics (e.g., phenacetin), antibiotics (e.g., amoxicillin and ciprofloxacin), antirheumatic agent D-penicillamine, potassium iodide, gold, and captopril. Diuretics and neuroleptics are the most often implicated cldasses.1
Diagnosis of BP is based on clinical presentation, histology, and direct and indirect immunofluorescence microscopy studies or BP180 enzyme-linked immunosorbent assay (ELISA). In the nonbullous phase of BP, there may be only subepidermal clefts, eosinophilic spongiosis, and/or dermal infiltrates of eosinophils.1,3 A biopsy of early bullae will show subepidermal split with a dermal inflammatory infiltrate of eosinophils and mononuclear cells on hematoxylin and eosin (H&E) stain.
With immunofluorescence, a punch biopsy is typically performed on uninvolved perilesional skin, ideally just adjacent to a bulla. Direct immunofluorescence should show continuous linear deposits of IgG and/or C3 complement along the epidermal basement membrane.1-3 In BP, the IgG subclasses are predominantly IgG4 and IgG1. Circulating anti-basement-membrane antibodies are present in about 60% to 80% of patients. Most commonly, IgG, but also IgA and IgE, may be detectable with indirect immunofluorescence.1 These autoantibodies will bind the epidermal side most frequently on salt-split skin.
Finally, ELISAs using recombinant proteins that include specific regions of BP antigens have a specificity for the disease that is greater than 90%, which is comparable to that for indirect immunofluorescence.1 Direct immunofluorescence, however, is usually the first-choice test because of its higher sensitivity.1,2
Differential diagnoses of BP in its nonbullous phase, which can present as nonspecific symptoms and signs, include drug reactions, contact dermatitis, prurigo simplex or nodularis, urticarial dermatoses, reactions to arthropod bites or stings, and scabies.
When bullous lesions form, however, the differential diagnoses include bullous arthropod bite reactions, Stevens-Johnson syndrome, bullous drug eruptions, porphyria cutanea tarda, and pseudoporphyria. In children, bullous impetigo, bullous mastocytosis, and inherited epidermolysis bullosa should be included.
Of course, it may be difficult to differentiate BP from other immunobullous diseases such as pemphigus vulgaris, paraneoplastic pemphigus, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, mucous-membrane cicatricial pemphigoid, and dermatitis herpetiformis. Therefore, immunopathologic findings, such as from direct and indirect immunofluorescence and ELISAs, are important in differentiating these conditions.1
Systemic corticosteroids are the mainstay of treatment. Our patient was treated with oral prednisone at 40 mg/day. Dosing is typically recommended at 0.5 to 1 mg/kg/day, which typically ameliorates symptoms within 1 to 2 weeks.1
Prednisone is then tapered over 6 to 9 months or longer to prevent flares.1,2 However, systemic corticosteroids have many significant side effects that are particularly intolerable for the elderly. About 3 weeks after the initiation of prednisone at 40 mg/day, our patient experienced a gastric perforation and gastrointestinal bleeding that resulted in admission to a medical intensive-care unit. A week prior to her admission, she was seen in the clinic with improvement of her BP but still demonstrated active new blister formation.
Therefore, as in this patient, other immunosuppressive drugs should be considered. Upon recovery, the patient was started on nicotinamide with tetracycline, as well as topical triamcinolone ointment, applied twice a day to all affected areas. This regimen is typically implemented in limited and localized disease, but erythromycin, penicillin, dapsone, sulfonamides, and topical immunomodulators, such as tacrolimus, are other possible options.
In patients with more extensive involvement or corticosteroid-refractory disease, immunosuppressive therapies, such as azathioprine, mycophenolate mofetil, methotrexate, chlorambucil, and cyclophosphamide, have shown some efficacy. Other possibilities for refractory BP include intravenous immunoglobulin, plasma exchange, and rituximab.1,2
Pemphigoid gestationis (PG), or herpes gestationis, is an autoimmune bullous condition that occurs in the second or third trimester of pregnancy or during the postpartum period. An estimated 1 in 50,000 pregnant women develops PG associated with human leukocyte antigen(HLA)-DR3 and -DR4.1
Most often, the eruption begins during the second trimester as erythematous urticarial plaques and papules around the umbilicus and extremities that then form annular or targetoid lesions. The lesions can spread to involve the trunk and extremities, as well as the palms and soles. However, the oral mucosa usually are spared. Tense bullae and vesicles form after and on top of these pink plaques.
Patients most often complain of intense itching that may come and go. In some cases, the disease can be quite mild and present shortly after delivery and resolve spontaneously. In this case, this was our patient’s second pregnancy, and she had had a mild, itchy, urticarial-type eruption after her first delivery that resolved quickly with topical triamcinolone ointment in a few days.
It is likely that she will experience recurrences of this condition in subsequent pregnancies as well. Menstrual periods or oral contraceptive medications may also incite flares.1,2 In addition, due to passive transfer of maternal antibodies, infants of mothers with PG may develop similar, mild skin involvement. This occurs in about 10% of newborns and may be associated with prematurity and neonates who are small for their gestational age.1
The pathogenesis of PG is attributed to complement-fixing autoantibodies of the IgG1 subclass that are targeted at the 180-kDa hemidesmosomal transmembrane protein, bullous pemphigoid antigen (BPAG2). These autoantibodies are anti-basement-membrane zone serum factors that induce deposition of C3 complement along the dermal-epidermal junction.1,2 It is unclear how or why these autoantibodies are produced during pregnancy or in the postpartum state.
Because they are known to bind amniotic basement membrane, studies are focusing on the potential cross-reactivity of placental tissue and skin.1
Differential diagnosis in a pregnant female includes polymorphic eruption of pregnancy (PEP) and drug eruption. PEP can appear similar to the urticarial plaques in PG. However, indirect immunofluorescence and ELISA tests can definitively distinguish PEP from PG.1
While both BP and PG present with tense bullae, they are typically clinically easy to differentiate since they present in very different patient populations. As mentioned earlier, BP is seen most commonly in elderly patients and may be drug-induced. PG should not occur in patient populations other than pregnant or postpartum women. The pathogenesis and histopathology of both conditions, however, are quite similar.
As in BP, diagnosis of PG is based on clinical presentation, histopathology, and immunologic studies. When immunobullous diseases are suspected, the best tests are direct immunofluorescence, indirect immunofluorescence, and ELISA. Often a biopsy with H&E stain is also obtained, but the majority of patients do not have classic findings.
Ideally, H&E staining would show subepidermal vesicles, but often there is mixed inflammatory infiltrate that frequently contains eosinophils. On direct immunofluorescence, which is obtained from perilesional skin, PG will show linear deposition of C3 complement along the basement membrane zone in 100% of patients and IgG deposition in 30%.1,2,4
As with BP, it is important to biopsy perilesional skin for direct immunofluorescence studies. Indirect immunofluorescence should detect anti-basement-membrane zone IgG1 autoantibodies in essentially 100% of patients with PG. ELISA can also be performed to assess antibody titers for BP180 at the NC16a domain.
Typically, PG is a self-limiting condition. Initial treatment should focus on controlling symptoms and preventing formation of new blisters. Mild cases may only require topical corticosteroids with antihistamines to control pruritus. For moderate to severe cases, systemic corticosteroids (d0.5 mg/kg of prednisone daily) often are necessary.
In some cases, flares can occur at delivery, which may require a temporary increase in prednisone and longer taper. Patients with a condition that is refractory to corticosteroids may improve with plasmapheresis during pregnancy. If the disease persists, which happens in very rare cases, treatment is similar to BP and steroid-sparing agents may be considered for long-term, chronic therapy.1,2
Our patient was started on 40 mg of oral prednisone daily, with partial response. The dosage was then increased to 60 mg daily, which suppressed any new bullae formation. Topical clobetasol cream was also prescribed and applied to itchy areas twice a day.
Due to severe itching, the patient also took 50 to 75 mg of oral hydroxyzine before bedtime for relief of these symptoms. She experienced rapid improvement over the next few weeks without any new lesions upon initiation of oral prednisone. Her drug therapy was tapered slowly over the next few weeks.
Tiffany Shih, MD, is a resident physician at the University of Minnesota in Minneapolis.
- Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed.
- Philadelphia, Pa.: Elsevier Saunders; 2012:439-441, 475-490.
- James WD, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:455-458.
- Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-481.
- Cobo MF, Santi CG, Maruta CW, Aoki V. Pemphigoid gestationis: clinical and laboratory evaluation. Clinics (Sao Paulo). 2009;64(11):1043-1047. Available at ncbi.nlm.nih.gov/pmc/articles/PMC2780519
All electronic documents accessed on November 4, 2014.