Pemphigoid

Bullous Pemphigoid (BP) is subepidermal blistering autoimmune disease primarily affects the skin, especially the lower abdomen, groin, and flexor surfaces of the extremities. Mucous membrane involvement is seen in 10%-40% of patients. The disease tends to persist for months or years with periods of exacerbation and remission.

The spectrum of presentations is extremely broad, but typically there is an itchy eruption with widespread blistering, and tense vesicles and bulla (blisters), with clear fluid (can be hemorrhagic) on apparently normal or slightly erythematous skin.

Lesions normally appear on the torso and flexures, particularly on the inner thighs. Blisters can range in size from a few millimeters to several centimeters, and although. pruritic, typically heal without scarring.

Sometimes erosions and crusting are seen. Also itchy bumps (papules) and crusts (plaques) can be seen with an annular or figurate pattern. A characteristic feature is that multiple bullae usually arise from large (palm-sized or larger), irregular, urticarial plaques. Mucosal (oral, ocular, genital) involvement is also sometimes present, but ocular involvement, is rare. BP can be difficult to diagnose in its ‘non-blistering’ stage, when just itchy, red, elevated patches are visible. Erosions are much less common than in pemphigus, and the Nikolsky sign is negative.

BP is characterized by spontaneous remissions followed by flares in disease activity that can persist for years. Even without therapy, BP is often self-limited, resolving after a period of many months to years, but may become very extensive.

Localized variants of the disease have been reported, most often limited to the lower extremities and usually affecting women. One such variant, localized vulvar pemphigoid, reported in girls aged 6 months to 8 years, presents with recurrent vulvar vesicles and ulcerations that do not result in scarring.

Bullous pemphigoid is distinguished from other blistering skin diseases, such as linear IgA dermatosis, epidermolysis bullosa acquisita, and cicatricial pemphigoid, by the following clinical items (it can also be distinguished by biopsy and certain immunological tests):

• Absence of atrophic scars
• Absence of head and neck involvement
• Relative absence of mucosal involvement

Epidemiology

• BP is the most frequent blistering disease of the skin (and mucosa) affecting typically the elderly (>65 years), but can occur at any age and in any race.
• Overall incidence: ± 7-10 new cases per million inhabitants per year.
• After the age of 70 incidence significantly increases.
• Relative risk for patients > 90 y have a 300-fold higher than those < 60 y.
• Women and men equally afflicted.
• Precipitating factors include trauma, burns, ionizing radiation, ultraviolet light, and certain drugs such as neuroleptics and diuretics, particularly lasix (furosemide), thiazides, and aldosterone antagonists.
• Correlations between BP flare activity and recurrence of underlying cancer suggest such an association in some patients.
• Even without therapy, BP can be self-limited, resolving after a period of many months to years, but is still a serious condition especially in the elderly.
• 1-y survival probability may be as high as 88.96% (standard error 5.21%), with a 95% confidence interval (75.6%, 94.2%) but other analyses have documented 1 year mortalities of as much as 25-30% in moderate to severe pemphigus even on therapy.
• Genetic predisposition, but not hereditary

Histology

The earliest lesion of BP is a blister arising in the lamina lucida, between the basal membrane of keratinocytes and the lamina densa. This is associated with loss of anchoring filaments and hemidesmosomes. Histologically, there is a superficial inflammatory cell infiltrate and a subepidermal blister without necrotic keratinocytes. The infiltrate consists of lymphocytes and histiocytes and is particularly rich in eosinophils. There is no scarring.

Approximately 70% to 80% of patients with active BP have circulating antibodies to one or more basement membrane zone antigens.

• Autoantibodies to BP180 (and BP230).
• BP180 and BP230 are two components of hemidesmosomes, junctional adhesion complexes.
• T cell autoreactive response to BP180 and BP230 regulate autoantibody production.
• On direct immunofluorescence, the antibodies are deposited in a thin linear pattern; and on immune electron microscopy, they are present in the lamina lucida. (By contrast, the antibodies to basement membrane zone antigens that are present in cutaneous lupus erythematosus are deposited in a granular pattern).

Mucous membrane pemphigoid (MMP) is a chronic autoimmune disorder characterized by blistering lesions that primarily affect the various mucous membranes of the body, but also affects the skin (MMP is now the preferred term for lesions only involving the mucosa). It is also known as Cicatricial Pemphigoid (CP), as it is often scarring.

The mucous membranes of the mouth and eyes are most often affected, but those of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Disease onset is usually between 40 and 70 years and oral lesions are seen as the initial manifestation of the disease in about two thirds of the cases. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat.

There is no racial or ethnic predilection, although most studies have demonstrated a female to male ratio of approximately 2:1. The diagnosis of MMP is mainly based on history, clinical examination and biopsy of the lesions.

Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis of pregnancy. The disease was originally named herpes gestationis on the basis of the morphological herpetiform feature of the blisters, but this term is a misnomer because PG is not related to or associated with any active or prior herpes virus infection. PG typically manifests during late pregnancy, with an abrupt onset of extremely pruritic urticarial papules and blisters on the abdomen and trunk, but lesions may appear any time during pregnancy, and dramatic flares can occur at or immediately after delivery. PG usually resolves spontaneously within weeks to months after delivery.

Pemphigoid Gestationis:

• Is a condition of pregnancy (childbearing age women).
• In the United States, PG has an estimated prevalence of 1 case in 50,000-60,000 pregnancies.
• No increase in fetal or maternal mortality has been demonstrated, although a greater prevalence of premature and small-for-gestational-age (SGA) babies is associated with PG.
• Patients with PG have a higher relative prevalence of other autoimmune diseases, including Hashimoto thyroiditis, Graves disease, and pernicious anemia.

What is LAD?

Linear IgA Disease (LAD) is a very rare autoimmune skin disease that causes blisters. These blisters can appear on the skin and in the mouth, and in other places like the groin fold, genitals, and eyes. It is caused by an autoimmune response in which a type of antibody called immunoglobulin A (IgA) is deposited between skin layers, where it shouldn’t be found in healthy skin.

Who gets LAD?

Both adults and children (even newborns) can get LAD, and it affects men and women equally. Usually, it starts in adulthood around the age of 60, but it can also begin in childhood, especially around ages of 4 and 5. Sometimes, LAD is triggered by specific medications, certain infection, or rarely vaccines. Most often, no cause can be identified. It is not hereditary or contagious.

How does LAD work?

IgA is a type of antibody that helps protect the body against infections. In LAD, IgA builds up in the wrong place and causes inflammation. This inflammation leads to blisters forming.

What are the symptoms of LAD?

• Blisters: small blisters, often arranged in clusters or rings.
• Itching: Many people with LAD experience itching before the blisters appear.

Where do the blisters appear?

• Children: Blisters often appear on the lower belly, genital and groin fold areas, feet, hands, and face, especially around the mouth.
• Adults: Blisters are more common on the trunk and limbs.

How long does LAD last?

• Children: LAD usually lasts about 3-4 years and often goes away on its own.
• Adults: LAD can last longer, up to 15 years, and may not always go away.

How is LAD diagnosed?

It can be difficult to diagnose LAD. Diagnosis is based on signs and symptoms of the disease and requires a skin biopsy with special tests (e.g. direct immunofluorescence). LAD can be sometimes misdiagnosed with other autoimmune blistering diseases (e.g. bullous pemphigoid or dermatitis herpetiformis).

How is LAD treated?

The main treatment for LAD is a medication called dapsone. Sometimes, other medications like sulfonamides and topical and/or systemic corticosteroids may also be used. In rare cased, LAD is refractory and requires more traditional immunosuppressants. Keeping blisters clean and covered can help prevent infection.

Key Features

Epidermolysis bullosa acquisita (EBA) is a rare subtype of autoimmune blistering disease. EBA is characterized by antibodies against type VII collagen, a component of the skin and mucous membranes. EBA is characterized by skin fragility, particularly in easily traumatized areas such as hands and feet. EBA can also present with rash, blisters, or mucous membrane involvement. Milia, small white pimple-like bumps, frequently occur in healing areas of skin.

Subtypes

EBA demonstrates several subtypes, though there can be overlapping features. The primary subtype is the mechanobullous variant, presenting as skin fragility in areas of trauma, particularly the hands and feet. The inflammatory variant can mimic another autoimmune blistering disease, bullous pemphigoid, presenting with any combination of itching, rash, and blisters. Other subtypes include isolated scalp involvement (Brunsting Perry-like EBA), mucosal involvement, linear IgA like-EBA which can mimic the autoimmune blistering disease linear IgA bullous dermatosis

Epidemiology

EBA is thought to occur in between 0.08 and 0.5 per million people per year. The disease mostly occurs in older adults, with a median age of onset of 50 years, although rarely it can occur in children and young adults. EBA may be associated with underlying inflammatory bowel disease.

Histology

Histologic findings in EBA tend to correlate with the clinic presentation. Mechanobullous lesions often present with subepidermal blistering with an absence of inflammatory cells, whereas inflammatory forms can present with an abundance of neutrophils, a type of inflammatory immune cell.

Diagnosis

EBA demonstrates positive direct immunofluorescence staining. However, as the staining of EBA is almost indistinguishable from other forms of pemphigoid using traditional techniques, a positive direct immunofluorescence is generally not sufficient to distinguish EBA from other pemphigoid diseases. EBA is confirmed by the presence of antibodies binding to the dermal side of salt-split skin on indirect immunofluorescence staining, and can also be confirmed by anti-type VII collagen antibodies in the blood. Notably, many patients with EBA fail to have high enough levels circulating anti-collagen VII antibodies to confirm the disease. Thus, a positive direct immunofluorescence study using salt-split skin with classical clinical findings is typically used to establish the tentative diagnosis, although other rare autoimmune blistering diseases such as p200 pemphigoid and anti-laminin 332 pemphigoid may demonstrate similar findings and should be ruled out when possible. 

Symptoms

EBA can present with skin fragility resulting in painful or itchy lesions at sites of trauma. This can lead to scarring and contractures over joints, leading to functional limitations. Mucosal lesions can present across different sites, leading to eye inflammation and scarring, oral sores or blisters, pain or trouble swallowing, or genital lesions which can cause scarring or strictures. In some cases, only one mucosal site will be involved.

Treatment

Treatment of EBA can vary significantly based on the clinical presentation. For example, inflammatory variants are often sensitive to therapies targeting neutrophils, such as dapsone and colchicine. Often, oral steroids are needed for acute control of the disease, allowing lesions to heal. Long term control of the disease often requires the use of immunosuppressive agents. This includes oral agents such as mycophenolate mofetil, azathioprine, or methotrexate, intravenous therapies such as rituximab or intravenous immunoglobulin (IVIg), or a combination of therapies. Successful use of dupilumab, a therapy recently approved for bullous pemphigoid, has been described in a few individual cases.