BULLOUS PEMPHIGIOD

An 84-year-old woman presents with a blistering rash. The rash began 1 week ago on her right hand, but it has progressed to her arm, upper chest, and abdomen. The rash is painless but intensely itchy, and it limits her ability to complete routine tasks. She has had no fever, no history of trauma, and no recent travel. She lives alone and uses an electric scooter to assist her with mobility. The patient relies on help from family and caretakers for the activities of daily living. She has a medical history of 100% estrogen-receptor-positive nonmetastatic breast cancer, ischemic heart disease, osteoporosis, and chronic renal insufficiency. The patient takes aspirin, isosorbide mononitrate, ramipril, simvastatin alendronate, and a calcium supplement. Her breast cancer is treated with an aromatase inhibitor. She has had no recent changes in her medication regimen and does not take any over-the-counter or herbal medications.
On physical examination, the patient appears frail but nontoxic. Her temperature is 98.4°F (36.9°C). Her heart has a regular rhythm with a rate of 88 bpm. Her blood pressure is 146/88 mm Hg and her respiratory rate is timed at 16 breaths/min. She has clear, equal bilateral breath sounds. There are no heart murmurs, but a loud S2 heart sound is heard. Her apical impulse is not displaced. The patient's abdomen is soft and nontender, and no appreciable organomegaly is detected. She has a deep, fixed 3-cm mass underlying the nipple of her right breast, with overlying skin puckering. She does not have any axillary lymphadenopathy. Her current breast examination is unchanged from her last documented examination. Examination of the skin reveals several tense bullae, excoriated papules, and vesicles ranging in size from a few millimeters to 3 centimeters over her right arm, anterior chest, and abdomen (see Figures 1 and 2). These bullae and vesicles rest on an erythematous base, and they contain clear fluid. There is no involvement of the mucous membranes and the Nikolsky sign (blistering of healthy-appearing skin when it is rubbed) is not elicited.
Laboratory tests are performed, which demonstrate normal erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and C-reactive protein (CRP) findings. She has a hemoglobin level of 12.7 g/dL (127 g/L), with a mild eosinophilia measured at 0.48 × 109/L. Her blood urea nitrogen is 28 mg/dL (10 mmol/L) and her creatinine level is 2.1 mg/dL (185.64 µmol/L). Her liver function tests are unremarkable.The patient in this case exhibited many factors suggestive of a diagnosis of bullous pemphigoid. Her advanced age, the clinical appearance of the skin lesions, and the subacute onset of an intensely pruritic, nonpainful rash were consistent with the diagnosis of bullous pemphigoid, and a skin biopsy sent for routine histology, direct immunofluorescence, and indirect immunofluorescence studies confirmed it. Histopathology of a subepidermal blister demonstrated an eosinophil-rich inflammatory infiltrate in the dermis. Viral and bacterial culture swabs from the blister fluid had a negative result, which excluded an infectious process (such as herpes zoster).
Bullous pemphigoid is the most common blistering autoimmune disorder in the Western world, with an estimated incidence of 6-7 cases per million in France and Germany, and an unknown incidence in the United States. It is a relatively benign condition that tends to run a waxing and waning course, with recurrent episodes of remission and relapse. It most commonly affects the elderly but can also rarely occur in younger patients and infants.[1,2,4] In cases of bullous pemphigoid, immunoglobulin G (IgG) autoantibodies attack the skin basement membrane zone, which induces an inflammatory response and activates the complement system. The 2 main antigenic targets that have been identified are known as bullous pemphigoid antigen 1 (BPAg1; a 230-kd protein) and bullous pemphigoid antigen 2 (BPAg2; a 180-kd protein). They are both components of the hemidesmosome and allow linkage of intermediate filaments to the basement membrane. Of these antigens, BPAg2 is thought to be the major contributor to the pathophysiology of bullous pemphigoid. Animal studies have shown failure of blistering to occur with antibodies induced solely against BPAg1.[2] In these cases, eosinophils are characteristically found on skin histopathology. They migrate to the area of injury by the activity of an eosinophil-specific chemokine called eotaxin.[2] Interleukin-16 (IL-16) is another cytokine that has been found in high concentrations in the serum of patients with bullous pemphigoid. IL-16 stimulates CD-4 helper cells and up-regulates interleukin-2 receptors.
Bullous pemphigoid can present acutely or subacutely with tense round or oval-shaped blisters and vesicles. Intensely itchy urticarial lesions can precede the bullae by days, weeks, or even months. The lesions of bullous pemphigoid may either be localized or generalized throughout the body, and they often affect the flexor areas of the limbs, as well as affecting the abdomen, chest, and medial thighs. Mucous membrane involvement may occur, but it is not common. The lesions heal without any scarring.[1,2] Although more commonly seen in pemphigus, the Nikolsky sign can also be occasionally seen in cases of pemphigoid. The Nikolsky sign is described as the separation of superficial skin from the deeper dermis with the application of gentle pressure.
A full history and physical examination is essential for recognizing the diagnosis and determining the etiology. Drug-induced bullous pemphigoid is well recognized and has many causes, including diuretics, antibiotics, and angiotensin-converting enzyme (ACE) inhibitors. Cessation of the drug normally prevents recurrence.[3] There is evidence of an association between bullous pemphigoid and malignancy; however, bullous pemphigoid itself has not been shown to increase the incidence of malignancy in age- and sex-matched controls.[1] Interestingly, Gül et al described a case of breast cancer with bone metastases presenting with bullous pemphigoid in a 62-year old-woman.[6] Bullous pemphigoid is a disease of the elderly and, of course, this population is much more prone to developing malignancy as well; therefore, a thorough examination for a possible associated malignancy is prudent.
The clinical differential diagnosis for bullous pemphigoid is broad and could include pemphigus vulgaris, linear immunoglobulin A (IgA) disease, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Blistering rashes can also be seen with impetigo, acute viral infections, drug eruptions, and herpes zoster. The patient's history and physical examination will help narrow down this differential. The patient's age, vital signs, the distribution of the blisters, and the nature of the blister (ie, tense or flaccid) all provide clues; however, testing is ultimately necessary, including immunofluorescence studies, histopathology, and viral and bacterial swabs.[1,4] In bullous pemphigoid, indirect immunofluorescence using serum will demonstrate circulating antibodies to the basement membrane zone of human skin or monkey esophagus substrate in a linear pattern in 70% of patients.[2] Skin biopsy of a blister will often reveal an eosinophilic inflammatory infiltrate, whilst direct immunofluorescence of normal skin adjacent to the lesion will show linear deposits of IgG and C3 at the basement membrane zone.
Other variants of bullous pemphigoid include gestational pemphigoid and cicatricial pemphigoid. Gestational pemphigoid occurs during pregnancy and leads to bullae or urticarial lesions on the abdomen, trunk and extremities, with mucous membrane sparing. The fetus is not affected and the disease regresses after pregnancy, although it may reappear with future pregnancies. Cicatricial pemphigoid rarely involves the skin and tends to affect mucous membranes, with ocular and oropharyngeal involvement, and it can lead to scarring and significant morbidity from blindness and airway obstruction.[4]
The treatment options available for bullous pemphigoid include oral steroids or topical steroid creams, antibiotics, steroid-sparing immunosuppressants (such as azathioprine, mycophenolate mofetil, and methotrexate), plasmapheresis, and immunoglobulin infusions. Steroidal options include the use of high-potency topical steroids, and oral steroid therapy with prednisone 0.5-1mg/kg/day can be used as well. In patients with a high risk of osteoporosis, calcium and vitamin D supplements with a bisphosphonate should be considered.[2] For acutely ill patients or those with extensive skin involvement, fluid replacement, thermoregulation, and infection management may be necessary. Most patients with bullous pemphigoid are elderly; they may have multiple comorbidities and may be taking multiple medications. Treatment should be carefully tailored to minimize side effects yet allow for adequate disease control.
A systematic review by Khumalo et al found potent topical steroids were safe and effective in patients with bullous pemphigoid, with less systemic side effects than oral steroid treatment.[5] The side effects of steroid treatment can include diabetes mellitus, peptic ulcer disease, glaucoma, cataract formation, and agranulocytosis. The prognosis of patients with bullous pemphigoid is generally very good. Disease remission can vary from 1-5 years with treatment.
The patient in this case was treated with high-potency topical steroids and experienced a good result. The patient tapered the medication over a period of several weeks, and she regularly followed up with her health care provider.You are examining a patient and suspect that she is suffering from bullous pemphigoid. Which of the following findings is MOST likely to be found in this patient?
Tense blisters are most likely to be found in cases of bullous pemphigoid, and they may be either localized or generalized. The blisters may be preceded by urticarial plaques or pruritus, and they are most often seen in the flexor areas of the limbs, medial thighs, abdomen, groin, and chest wall. Mucosal involvement is uncommon. The lesions of bullous pemphigoid typically do not form scars. Pyrexia may be present if bullae are infected, but this is not typical. A dermatomal distribution would point to herpes zoster infection.
You are examining a 76-year-old patient who presented with a vesiculobullous rash on his elbows and knees that began 2 months ago. The rash is painful and limits his activities. His history reveals that he has experienced similar episodes in the past. You diagnose this patient with bullous pemphigoid, which is confirmed by histopathologic analysis and direct immunofluorescence testing. Which of the following choices would be the mainstay of treatment for this patient?While many treatment modalities exist, steroids are the mainstay of treatment. The treatment should be tailored to each individual patient, and it should account for any underlying medical conditions and medications taken.