Diagnostic Dilemma: Bullous Pemphigoid

Department Editor: Tania Phillips, MD, FRCPC Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Describe an unusual presentation of bullous pemphigoid 2. Diagnose bullous pemphigoid 3. Describe the pathogenesis of bullous pemphigoid 4. Discuss the management of bullous pemphigoid. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Lin and Phillips disclose no financial conflicts. Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications, LLC, designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by February 1, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: February 1, 2002 Expiration date: February 1, 2003 Presentation A 77-year-old Chinese man with a history of Parkinson’s disease presented with a two-month history of blisters on his feet and ankles. He did not have any blisters in his mouth or on his genitalia. His medications included zinc sulfate, vitamin C, multivitamins, bromocriptine (Parlodel), oxybutynin chloride (Ditropan), carbidopa-levodopa (Sinemet), docusate sodium, and iron supplements. He had no family history of blistering disease. Physical examination revealed a slim, elderly, Asian gentleman. His head, neck, oral mucosa, chest, abdomen, back, upper extremities, and genitalia were normal. His feet showed macular hyperpigmentation in a circular pattern on the posterior right heel and right dorsal foot. There were two healing bullae on the left foot. One bullae was almost completely reepithelialized. The other was flaccid, filled with turbid fluid, and measured six centimeters in diameter (Figures 1 and 2). Initial diagnostic considerations included bullous drug eruption and bullous pemphigoid. Investigations Two biopsies were performed on the medial aspect of the left foot. Blister contents were cultured and showed no growth. Routinely stained biopsy of the lesion showed epidermal-dermal separation, eosinophil-rich vesicle fluid, and numerous superficial and deep eosinophils, consistent with bullous pemphigoid. Direct IMF of perilesional skin was negative. Diagnosis The patient was diagnosed with bullous pemphigoid (BP) on the basis of clinical and histopathologic findings. Discussion Epidemiology. BP is a blistering disorder that mainly affects patients between the ages of 60 to 80 years,1 although rare cases in children have been reported.26,31,32,58 BP is thought to affect both genders and all races and ethnic groups equally.30 However, a recent report suggested that the risk for BP is increased in men by 2:1, especially in those above 60 years of age.64 Clinical features. History. Classic BP is a chronic, self-limited, subepidermal, blistering disease.1,30 The course tends to be benign and rarely life threatening, even without treatment, unlike pemphigus vulgaris.10,30 The blistering lesions often present with pruritic, urticarial, papular lesions that progress to bullae over the period of weeks to months. The bullae then may appear as a sudden generalized eruption. Pruritus may be moderate to severe in the prodrome. Eroded bullous lesions may be tender. Usually there are no constitutional symptoms. Physical examination. The areas most commonly involved are the axillae, abdomen, thighs, groin, lower legs, and flexural surfaces of the arms. Often the lower legs are the first to be affected. Mucous membranes (mouth, anus, vagina) are not commonly affected but, when involved, can scar.30 Prodromal changes may proceed the bullae and vesicular changes by months and include erythematous papules and plaques, urticaria, eczematous, and crusted lesions. Bullae are tense, oval or round, firm topped, and large with an erythematous, normal, or urticarial base.1,30 They contain serous or hemorrhagic fluid. The lesions may be generalized or localized, as in our patient, and may be scattered or grouped in serpiginous and annular configurations.30 Ruptured bullae may present as oozing or bleeding erosions that become crusted. Nikolsky’s sign (upper layers of skin are easily slipped laterally by rubbing or slight pressure) is usually negative.30 Pathogenesis. Patients often have an autoantibody that binds to the 230 kd (50–70% of cases)13 and the 180 kd (30–50% of cases)13 antigen of the epidermal basement membrane.7,8 Circulating IgG antibody develops in 65 percent9 to 90 percent30,45–47 of patients with BP, with false positive occurring in up to three percent of controls.46,48,49 All IgG subclasses are present, although most of the complement-fixation activity is from the IgG3 lineage.30 Antibody titers do not reflect disease activity.50 Antibodies react to all stratified squamous epithelia.30 Regional variants of the distribution of BP antigen61 and of in-vivo deposition of antibody62 have been reported. The blister fluid contains elevated levels of interferon, suggesting presence of activated T lymphocytes43 and implicating a cell-mediated immune reaction in addition to the antibody reaction to components of the basement membrane zone in the pathogenesis of this disease.40 For drug-induced BP, it was proposed that development of an antigenic hapten to a cell site from a medication stimulates an immune response.15,26 Many inducing medications contain a sulfhydryl group that cleaves the epidermal cementing substance, resulting in an autoantibody. Many believe that the sulfhydryl groups are a necessary criterion for drug-induced BP.21,25 Penicillamine,15–17 furosemide,18-20 captopril,21 enalapril,9 penicillin and its derivatives,22–24 sulfasalazine,25 salicylazosulfapyridine,26 phenacetin,27 nalidixic acid,28 and topical fluorouracil29 have all been reported to induce bullous pemphigoid. Penicillamine and furosemide are the most frequent culprits.9 Ultraviolet light56 has also been implicated in causing BP. Laboratory features. BP is associated with peripheral blood eosinophilia.5 An elevated IgE level is found in 37 to 70 percent of bullous pemphigoid patients.6,11,12 Sixty-five to ninety percent of cases of BP patients exhibit serum anti-basement membrane zone antibodies directed against 230 kd or 180 kd antigen in the lamina lucida.13,14,30,45–47 Serum levels of complement components remain normal.53 In the blister fluid, there is marked reduction of components of C1 through C7 and mild reduction of C8 and C9.53 Light microscopy. Subepidermal bullae are present. Dermal changes include neutrophilic, eosinophilic, and lymphocytic infiltrates. Neutrophils may be present in “Indian-file” at the epidermal-dermal junction. Electron microscopy. Electron microscopy usually shows a split in the lamina lucida of the basement membrane. There may be basal cellular changes of inter- and intracellular edema and subjacent endothelial cells.30 Eosinophil and histiocyte infiltration may be present.30 The basal lamina tends to remain on the floor of the early bullae, then disintegrates eventually.30 Histopathology and immunofluorescence (IF). There is usually a subepidermal bullae with eosinophilia.30 The upper dermis often has helper/inducer T lymphocytic, neutrophilic, and histiocytic infiltrate of varying severity.30,40 Epidermal necrosis is not observed.30 Direct IF of involved and uninvolved (less characteristically) skin demonstrates a linear deposition of immunoglobulins, typically IgG, and complement components from the classic and alternative pathways in the same pattern.51 Linear deposition of IgG or complement components (or both) are highly specific and reasonably sensitive for detecting BP.30 Direct immunofluorescence is generally agreed to be the principal diagnostic test for BP. However, Wiegand, et al.,59 found that direct IF was a less useful diagnostic test in localized BP than in generalized BP.59 In their study, localized disease had a tendency for weak or even negative direct IF, and the amount of immunoreactant roughly correlated with the extent of the disease. Light microscopy may be a more reliable diagnostic test than IF in localized lesions.59 Treatment. Although usually having a benign course, untreated BP can cause significant morbidity and can even be fatal.40 Mortality rate for patients older than 65 years of age is reported to be 27 percent.41 There are many treatment options depending on the extent of involvement. Topical steroids alone (clobetasol propionate followed by maintenance therapy with less potent topical corticosteroids) are successful in treatment of localized BP.63 Localized BP35 and generalized BP35 have been treated successfully by tetracycline alone, combinations of tetracycline with nicotinamide, niacinamide, erythromycin, and/or topical steroids.31,33,35-37,60 Dapsone has also been reported to treat BP effectively.30,38 Doxycycline has been reported as unsuccessful in treating BP, which was attributed to differences in anti-inflammatory, immunosuppressive, or pharmacokinetic properties between doxycycline and tetracycline.39 Systemic corticosteroids (prednisone, prednisolone) in moderate to high doses (40 to 240mg per day) have been traditionally used to treat generalized BP.10,30,31,41,42 Other immunosuppressants, such as azathioprine, methotrexate, cyclophosphamide, and chlorambucil, can be used alone or as steroid-sparing agents.31,40 Side effects of systemic corticosteroids and immunosuppressives in some cases may actually be worse than the disease itself, especially in elderly patients with complicated preexisting medical conditions.33,34 Management For patient comfort, bullae were drained under sterile conditions. Lesions were treated with topical clobetasol propionate cream 0.05 percent. The patient improved dramatically with no recurrence of bullae. There were residual hyperpigmented patches in the areas of skin previously involved by bullous lesions on his lower extremities (Figures 3 and 4). We advised the patient to stop the topical steroids but to resume them immediately if the lesions recurred. How to obtain educational credits by reading this article Learning Assessment: Successful completion entails scoring at least 70 percent on the questions, completing the entire evaluation form and submitting it online or printing it off and mailing or faxing it to the correct address listed below. Certificates will be mailed to those who successfully complete the learning assessment by February 1, 2003. Fax the completed form to: (610) 560-0501 or mail the completed form to: Trish Levy, CME Director HMP Communications, LLC 83 General Warren Blvd. Suite 100 Malvern, PA 19355 Questions 1. What is the hallmark lesion in bullous pemphigoid? A. Scaly skin B. Superficial erosions C. Tense bullae appearing on an erythematous, normal, or urticarial base D. Macular hyperpigmentation E. Pustules 2. Prodromal signs in bullous pemphigoid include which of the following? A. Erythematous papules and plaques B. Urticaria C. Crusted lesions D. All of the above 3. What areas of the body are most commonly involved in bullous pemphigoid? A. Axillae and the flexural surfaces of the arms B. Abdomen C. Thighs and lower legs D. Groin E. All of the above 4. What is the presumed pathogenesis of bullous pemphigoid? A. Intercellular IgG B. Basement membrane IgG and complement C. Linear IgA D. IgG to desmoglein 3 E. All of the above 5. Which autoantigen is thought to be involved in the pathogenesis of bullous pemphigoid? A. BP antigen 1, 230 kD B. BP antigen 2, 180 kD C. BP antigen 3, 90 kD D. A and B E. All of the above 6. What is the treatment of bullous pemphigoid? A. Topical steroids B. Oral prednisone C. Tetracycline and nicotinamide D. Cyclophosphamide E. All of the above are acceptable depending on extent and severity of disease Bullous Pemphigoid Answer Form and Evaluation Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions above) Click or circle one letter for each answer: 1. A B C D E 2. A B C D 3. A B C D E 4. A B C D E 5. A B C D E 6. A B C D E Evaluation — Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning objectives: 4 3 2 1 Effectiveness of the teaching/learning methods: 4 3 2 1 This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Describe an unusual presentation of bullous pemphigoid? YES NO 2. Diagnose bullous pemphigoid? YES NO 3. Describe the pathogenesis of bullous pemphigoid? YES NO 4. Discuss the management of bullous pemphigoid? YES NO What questions do you still have?________________________________________________________ How will you use what you have learned from this activity?___________________________________________________ All tests must be received by 2/1/03.