Pemphigoid is a group of rare autoimmune blistering diseases of the skin and mucous membranes. As its name indicates, pemphigoid is similar in general appearance to pemphigus, however unlike pemphigus, pemphigoid does not feature acantholysis, a loss of connections between skin cells.
Pemphigoid is more common than pemphigus and is slightly more common in women than in men. It is also more common in people older than 70 than it is in younger people.
Classification The forms of pemphigoid are considered to be connective tissue autoimmune skin diseases. There are several types: Gestational pemphigoid (PG); formerly called Herpes gestationis Bullous pemphigoid (BP) Mucous membrane pemphigoid (MMP); also called cicatricial pemphigoid
Bullous and mucous membrane pemphigoid usually affect persons who are over age 60. Gestational pemphigoid occurs during pregnancy, typically in the second or third trimester, or immediately following pregnancy.
Pemphigoid is usually considered to be mediated by IgG, but IgA-mediated forms have also been described.
IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.
Bullous pemphigoid
Bullous pemphigoid (BP) is a rare and chronic autoimmune disorder characterised by large sub-epidermal blisters called bullae that predominantly involves the skin and less commonly the mucous membranes. It is the most common type of the pemphigoid group, representing 80% of sub-epidermal immunobullous cases. It is more commonly known as cutaneous pemphigoid.
Presentation Primary lesions of small and large blisters, known as vesicles and bullae, are found on the skin and sometimes on the mucous membranes.
Non-bullous pemphigoid In some patients, pemphigoid starts off with cutaneous manifestations of bullous pemphigoid without bullae, as the only sign of the disease. Pruritic eczematous, papular, or urticaria-like skin lesions may also persist for weeks to months.
Bullous phase The bullous stage of BP shows vesicles and bulla, appearing on apparently normal or erythematous skin, predominantly at the flexural aspects of the extremities and the lower trunk. Mucosal lesions, which typically are erosions of the oral mucosa, are present in 10 to 30 percent of patients. Occasionally, the blister fluid becomes blood-tinged. The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas, together with urticarial and infiltrated papules and plaques in an annular or figurate pattern.
Homology between bullous pemphigoid antigens in the skin and neuronal antigens in the central nervous system has been proposed as a cause for the observed link between bullous pemphigoid and neurologic disease; this could be explained by an underlying genetic predisposition. Patients with bullous pemphigoid usually present with two or more other chronic diseases such as neurological disorders (dementia, Parkinson's disease, or stroke). However, further studies are necessary to explore the relationship between these disorders.
Cause The pathogenetic mechanism of blister formation is known; the trigger to the formation of the antibodies to the hemidesmosome antigens is still unknown. Most bullous pemphigoid cases are due to autoantibodies (mostly IgG) directed at antigens (BP180 and BP230) arranged at the dermal-epidermal junction. However, most commonly, drugs can be one of the causes of bullous pemphigoid, such as thiazide diuretics, antibiotics (e.g., penicillins, vancomycin), nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) and possibly angiotensin receptor blockers (ARBs, e.g., valsartan).
The implicated drugs include:
Penicillin derivatives Sulfasalazine Ibuprofen Phenacetin Enalapril Captopril Lisinopril Gabapentin Novoscabin Levobunolol ophthalmic solution DPT vaccine Influenza, tetanus, and other vaccinations. Influenza vaccination does not appear to be an important trigger for bullous pemphigoid. Homeopathy regimen Nifedipine 5-aminosalicylic acid Doxazosin Serratiopeptidase Losartan Cephalexin Bumetanide Fluoxetine Chloroquine Antipsychotic drugs (neuroleptics) Enoxaparin Ciprofloxacin Furosemide (frusemide) Penicillamine Gliptin plus metformin Intravenous iodine Etanercept Levofloxacin Topical fluorouracil
Trauma, burns, lymphedema, phototherapy, and radiation have been implicated in a very small number of cases.
Pathophysiology The pathophysiology of bullous pemphigoid consists of two major components: immunologic and inflammatory. In the immunologic component, autoantibodies act against the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2 or type XVII collagen), located in the lamina lucida of the basement membrane zone. These antigens play an important role in the adhesion complexes that promote epithelial-stromal adhesion. The predominant subclass of antibodies that acts against the antigens is IgG4. IgG1 and IgG2 antibodies are less frequently detected compared to IgG4 antibodies, while IgG3 antibodies are usually absent. When the autoantibodies bind specifically to the target antigens, the complement system and mast cells are activated, representing the inflammatory component. Inflammatory cells such as neutrophils and eosinophils are then attracted to the affected area. They are postulated to release proteolytic enzymes which degrade the hemidesmosomal proteins, resulting in blister formation.
Other potential contributory factors including genetic factors, environmental exposures to infections and drugs as well as the phenomenon of epitope spreading are also known to cause bullous pemphigoid.
Diagnosis Diagnosis of bullous pemphigoid includes clinical assessment, skin biopsy for histopathology and direct immunofluorescence, indirect immunofluorescence and the ELISA test. Among all, direct immunofluorescence is the gold standard for diagnosis of bullous pemphigoid.
Clinical assessment For patients greater than 70 years old
Blistering skin disease characterized by the presence of tense blisters and erosions that occur without another identifiable cause and rarely on mucosa. Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques
Histopathology Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E) staining.
Typical histopathologic findings include:
Sub-epidermal split with numerous eosinophils within the cleft. A superficial dermal inflammatory cell infiltration of variable intensity with lymphocytes, eosinophils, and neutrophils. Eosinophilic spongiosis (specifically in early lesions or may be seen in clinically erythematous skin surrounding the blister)
Direct immunofluorescence Direct immunofluorescence (DIF) studies involves directly detecting tissue bound antibodies. Biopsy specimens for DIF should be taken from perilesional skin instead of lesional skin for H&E histopathologic evaluation. DIF specimens should be placed in Michel's solution or Zeuss transport media instead of formalin.
DIF of bullous pemphigoid will show the presence of fine, continuous and linear deposits of IgG and/or C3 along the epidermal basement membrane. Other classes of immunoglobulins such as IgM and IgA are present in approximately 20% of cases and usually are less intense. In some cases with the deposits of IgA, patient may have oral lesion. At early stages of the disease, only C3 may be present.
Indirect immunofluorescence Indirect immunofluorescence is used to detect circulating antibodies targeting the antigens at the basement membrane zone in patients with pemphigoid. In this procedure, patient's serum is collected and overlaid on salt-split normal human skin and incubated. Following this, the specimen will be stained for fluorescent detection of antibodies.
In bullous pemphigoid, circulating IgG targeting the basement membrane, mainly BP180 and BP230 hemidesmosomal proteins are detectable in 60-80% of patients. IgA and IgE classes can also be detected, but less frequently.
Enzyme-linked immunosorbent assay (ELISA) ELISA for bullous pemphigoid are commercially available to test for circulating Ig against NC16A domain of BP180 and BP230, known as bullous pemphigoid antigen 2 [BPAg2] and bullous pemphigoid antigen 1 [BPAg1] respectively. Antibodies to BP180NC16A domain is useful for the diagnosis of bullous pemphigoid as it has a sensitivity of 89% and specificity of 98%.
Detection of BP180 and/or BP230 antibodies in serum does not give a confirmative diagnosis of bullous pemphigoid. A study has reported that 7% were tested positive for one or both autoantibodies in one series of 337 people without bullous pemphigoid. ELISA findings should be correlated with DIF to reduce the risk of misdiagnosis.
Treatment The treatment for bullous pemphigoid include:
1. Corticosteroids
i. Topical Corticosteroids
ii. Systemic corticosteroids
2. Glucocorticoid-sparing drugs
i. Immunosuppressive drugs
ii. Anti-inflammatory drugs
3. Biologic therapy
i. Intravenous immunoglobulin
ii. Rituximab
Among all, topical or systemic corticosteroids are considered as the first line therapy in controlling bullous pemphigoid. Other drugs and immunomodulatory therapies are often used as adjunct to minimize the adverse effect of long term use of corticosteroids and improve the healing of the disease.
There are several factors that have to be taken into account when choosing the therapies given to the patient: (a) patient's age (b) underlying disease such as hypertension, diabetes mellitus and other cardiovascular disease (c) side effect with the use of drugs (d) patient's ability to compliant to the therapy (d) severity and extent of disease (e) cost of drugs.
Corticosteroids High potency topical corticosteroid is preferred as the first line treatment due to its efficacy and fewer systemic adverse effects when compared to systemic corticosteroids. Studies have shown that patients with extensive bullous pemphigoid (defined as >10 new bullae per day) treated with topical corticosteroids (Topical Clobetasol Propionate 0.05% cream) had better clinical outcomes than patients with extensive bullae pemphigoid who were treated with systemic glucocorticoid therapy (Prednisone).
Systemic glucocorticoids can be used for patients when there are factors that make the use of topical corticosteroids not feasible, such as elderly patient inability to apply the cream on their own, cost or patient's own preference.
Topical Corticosteroids Topical Clobetasol Propionate 0.05% cream is usually used and applied twice daily. A study by Joly et al. demonstrated that the use of 10 to 20g of Clobetasol Propionate per day for moderate disease and 20 to 30g per day for extensive disease until 15 days after disease control, then tapered to discontinuation over four months was as effective as the standard regime (40g per day tapered slowly over 12 months).
Systemic corticosteroids Prednisone is usually used to treat bullous pemphigoid. The dose varies between 0.2 and 0.5 mg/kg/day and will continue until active inflammation, new blister formation, pruritus has stopped for at least 2 weeks. The dose is then slowly tapered over the months. Initially, prednisolone can be reduced by relative large amounts (approximately 10 mg) and smaller amount (2.5–5 mg) subsequently. Should the patient develop flare up of the lesion, the dose should be increased to the previous level or higher and maintained longer before further, slower tapering.
Glucocorticoid sparing drugs