At the dermatology clinic, 58 year old Alan presents complaining of painful lesions on his skin and mouth for the past two months. On examination, there are flaccid bullae with erosions all over his trunk and extremities, as well as erosions on the oral and gingival mucosa. When lateral pressure is applied to a lesion, the outermost layer seems to slough off.
On the same day, 17 year old Gabriella comes in with an intensely itchy rash that appeared a couple of weeks ago. She has also experienced frequent nausea and diarrhea after meals. Physical examination shows multiple papules, vesicles, and bullae on both of her knees, forearms, and elbows, as well as her back and buttocks. Lab tests reveal elevated levels of anti-gliadin IgA and IgM. Based on the initial presentation, Alan and Gabriella seem to have some form of vesiculobullous or desquamating skin disorder.
Okay, first, let’s talk about physiology real quick. Normally, the skin is divided into three main layers, the epidermis, dermis, and hypodermis. The hypodermis is made of fat and connective tissue that anchors the skin to the underlying muscle. Above the hypodermis is the dermis, containing hair follicles, nerve endings, glands, blood and lymph vessels. And above the dermis is the epidermis, which contains 5 layers of developing keratinocytes.
Keratinocytes start their life at the lowest layer of the epidermis, so the stratum basale or basal layer. As keratinocytes in the stratum basale mature, they migrate into the next layers of the epidermis, called the stratum spinosum, stratum granulosum, stratum lucidum, and finally, the stratum corneum, which is the uppermost and thickest epidermal layer.
Before we dive into the various inflammatory skin disorders, there are several high yield terms to describe skin lesions. The most important here are the vesicles, which are up to 1 centimeter in diameter and look like clear blisters filled with fluid, and bullae, which are fluid-filled blisters larger than 1 centimeter.
All right then, onto vesiculobullous and desquamating skin disorders! Let’s start with autoimmune blistering diseases, which are a group of autoimmune disorders that affect the skin and mucous membrane like those found in the mouth. They are caused by a type II hypersensitivity reaction. That’s when the immune system B cells produce antibodies that bind to the body's own proteins. A disorder belonging to this group is pemphigus vulgaris, which is mainly seen in adults between the age of 40 and 60.
Now normally, the epidermal cells, particularly those in stratum spinosum, are bound together by proteins called desmosomes, while other proteins called hemidesmosomes anchor basal cells to the basement membrane. In pemphigus vulgaris, there are IgG autoantibodies that can bind to the desmosome proteins, desmoglein 1 and 3.
As a result, the epidermal cells become separated from each other; this phenomenon is called acantholysis. Now, in pemphigus vulgaris, the hemidesmosomes are not affected, so cells remain attached to the basement membrane. Upon histology, this kind of looks like a row of tombstones, and is called tombstoning.
Now, the result is the formation of intraepidermal blisters or bullae characteristic of pemphigus vulgaris. These blisters or bullae are flaccid, meaning that they may easily slough off and give rise to very painful erosions. Erosions are frequently seen in the oral mucosa, which can make it hard for these individuals to eat.
Now for diagnosis, a classic sign of pemphigus vulgaris is the Nikolsky sign. This is when lateral pressure is applied to the lesion, and it causes a split to form between the upper and lower layers of the epidermis. In addition, a skin biopsy can be performed to look for signs of acantholysis and tombstoning. Direct immunofluorescence can also be useful; that’s where antibodies marked with fluorescent molecules are used to tag the autoreactive IgG antibodies, which are attaching to the intercellular desmosomes. This appears with a reticular or ‘fish net’ staining pattern.
Treatment for pemphigus vulgaris can include both topical and systemic corticosteroids, immunosuppressants like azathioprine or mycophenolate, and rituximab, a monoclonal antibody that binds to B cells and inhibits the production of anti-desmosomal IgG antibodies. If not treated, pemphigus vulgaris can be fatal, usually due to the lesions becoming infected.
Bullous pemphigoid is another autoimmune blistering disease typically affecting those over 60 years of age but is more common than pemphigus vulgaris. Another difference between the two diseases is that in bullous pemphigoid, the autoantibodies bind to hemidesmosomes. This causes the basal cells to separate from the basement membrane, and a split forms between the dermis and epidermis, resulting in subepidermal bullae.
A trick to remember this is to think of the word ‘below’ when thinking of ‘bullous’ pemphigoid, since the bullae are ‘below’ the epidermis and basement membrane. These bullae are tense, so they don’t break off easily. Now, bear in mind that bullous pemphigoid is milder than pemphigus vulgaris, and the oral mucosa is spared.
Now, for diagnosis, it’s high yield to know that Nikolsky sign is negative. In addition, a skin biopsy and immunofluorescence can be done, which will show a linear IgG deposition on the dermal-epidermal junction. In terms of treatment, bullous pemphigoid responds well to corticosteroids.