BULLOUS PEMPHIGOID

By Gary M. White, MD

Bullous Pemphigoid


Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease associated with autoantibodies to the hemidesmosomal bullous pemphigoid antigens 180 and 230 located in the basement membrane zone (BMZ).

Clinical

Localized or widespread urticarial plaques with overlying tense bulla or erosions in an elderly person is characteristic. Oral involvement is less common than in pemphigus vulgaris. Rarely, BP may preferentially affect the sun-exposed areas or be induced by UVB. In patients who scratch too much, prurigo nodularis lesions may develop, called pemphigoid nodularis. The clinical presentation of BP in children is similar to that in adults except there is more frequently involvement acrally and of the mucous membranes. A very rare form of erythrodermic BP has been reported (BJD 1995;133;967). BP is the most common bullous disease to coexist with psoriasis [BJD 1996;135;738].

Some patients present with urticarial plaques. They may be small, e.g. 1-2 cm or large, spanning > 10 cm. The diagnosis is sometimes not suspected as urticarial BP can present before any blisters.BP may rarely present with oral erosion alone in the elderly [BJD 1999;141;157].

The Asboe-Hansen sign is positive: pressure applied to the top of the blister causes lateral extension of a blister.

Differential Diagnosis

Consider among others epidermolysis bullosa acquisita and Anti-p200 Pemphigoid.

Neurologic

Neurologic disorders, e.g. Parkinson's disease, dementia, stroke, multiple sclerosis, are much higher in patients with BP than controls. It is thought that neurodegenerative processes uncover BPAg1-n, an alternatively spliced form of BPAg1-e that stabilizes the cytoskeleton of sensory neurons, generating autoantibodies that may subsequently lead to BP by cross-reacting with BPAg1-e. A study reported an associated occurrence of BP in 21% cases of neurological disorder (8% stroke, 7% dementia, 3% Parkinsonism, 2% epilepsy and 1% multiple sclerosis) of more than a year's duration [J Invest Dermatol. 2011;131:631–6].

Mortality

Mortality is higher than in controls. Infection is the cause of mortality in up to 60% of cases. Pneumonia is 3 times higher than the general population. Older age, poor general condition, dementia and the use of high-dose corticosteroids are risk factors [JAAD 2015;72;834].

Drug-Induced Bullous Pemphigoid

Both topical and oral iodine have been reported to cause BP. Rarely, BP may be drug-induced (e.g. everolimus, sirolimus furosemide, penicillamine, captopril, etc.). Dipeptidyl peptidase-4 inhibitors used to treat diabetes have been reported to trigger BP, specifically linagliptin, sitagliptin and vildagliptin. Immune checkpoint inhibitors may cause BP, e.g., nivolumab.

Workup

DIF is more sensitive (91%) than IIF (76%) for the diagnosis of BP. Nonbullous lesional or perilesional skin (with a 1 cm of a bulla) from the trunk is the best for DIF. For H&E, biopsying a small intact blister is best. Second choice is the edge of a larger blister along with adjacent nonbullous skin. DIF shows IgG and/or C3 along the BMZ in 90% of of cases. If DIF does not confirm, then indirect IIF should be performed [J Am Acad Dermatol. 2013 Nov;69(5):748-53]. Complete workup includes exclusion of EBA via split skin immunoflourescence or immunoelectron microscopy. Helpful blood work includes CBC, LFTs, creatinine, hepatitis serologies, TMTP (if azathioprine is your favorite steroid sparing agent) and possibly ppd.

See also anti-p200 pemphigoid.

Treatment

Topical Steroids

A high potency topical steroid (e.g. clobetasol cream 20-40 grams/day) is considered first line therapy for bullous pemphigoid, even in extensive disease [NEJM 2002;346:321-7]. Skin atrophy has been quoted to occur in 15% of patients.

Systemic Steroids

Prednisone 0.5-0.75 mg/kg/day may be given for widespread disease. It is fast-acting and can control blistering within 1-2 weeks. Going above 0.75 mg/kg/day usually has little benefit, has a higher mortality and should usually be avoided. After the disease has been brought under control, the prednisone should be tapered to the lowest effective dose. Be cautious in tapering an oral steroid too rapidly in the elderly as adrenal crisis can rarely occur. If the disease cannot be controlled with prednisone, if side effects are a problem, or the prednisone can’t be tapered to a low dose, a steroid sparing agent may be needed. Choices are listed below.

Tetracyclines

One of the tetracyclines can be effective, e.g. minocycline 100 mg BID, doxycycline 100 mg BID or tetracycline 500 BID. Some believe minocycline is the most potent of the tetracyclines, but blue pigmentation of the skin commonly occurs. BLISTER Trial is ongoing [Br J Dermatol. 2015 Feb 13]. The oral tetracyclines are often combined with niacinamide (0.5-2 grams after each meal and QHS)

Azathioprine

Azathioprine added to systemic steroids in one study allowed the dose of prednisone to be cut in half. The typical dose is up to 2.5 mg/kg/day.

Mycophenolate mofetil

Mycophenolate mofetil can be given.

Methotrexate

Methotrexate (5-15 mg/week) may be used and can be very effective. It may be given alone, as an adjunct to prednisone or in other combinations, e.g. with minocycline.

Rituximab plus IVIg

12 patients were treated with a combination therapy of rituximab plus IVIg [JAAD 2016;74;700]. All patients sustained a complete remission. With a 6 year follow-up, there were no adverse events, infections or hospitalizations. It seems these two medications work together. The rituximab depletes the B cells and the IVIg, among other effects, provides immunoprophylaxis, especially in the early stages.

The first 6 months of the protocol is as follows: The patient is initially given an infusion of IVIg (2 g/kg/cycle for immunoprophylaxis. After this first infusion of IVIg, the patient is started on weekly RTX infusions (375 mg/m2) for 8 weeks followed by monthly RTX infusions for 4 months. During this entire 6 months, the patient continues to receive IVIg infusions monthly.

Omalizumab

Recently, several studies have emphasized the importance of IgE autoantibodies (in addition to IgG) against basal membrane proteins BP180 and Bp230 in the pathogenesis of BP. Thus, omalizumab, an anti-IgE antibody may be used in the treatment of BP. A retrospective study of 6 patients concluded that omalizumab neutralizes the activity of IgE in patients with BP and improves the control of their disease activity [JAAD 2014;71;468–474]. In one study of two patients, omalizumab 300 mg subcutaneously every 3 weeks was used successfully as a steroid-sparing agent [JEADV 2016;30;1778]. Complete clearing may occur within 3 weeks. Omalizumab may be particularly beneficial for patients with a high eosinophil count and elevate serum IgE.

Dapsone

Dapsone's use in the treatment of BP appears to be limited.

Immunoadsorption

Immunoadsorption or the depleting of autoantibodies is an effective and relatively safe treatment of bullous pemphigoid and may be combined with other therapies [JAAD 2013;71:1018].

Prognosis

Overall mortality is increased with the diagnosis of bullous pemphigoid. Older age > 70 years, low Karnofsky performance scale and neurologic disease confer a higher mortality. Death is attributed to infection in the majority of cases.

Infection is seen in about half of patients and is associated with demential and poor general function [J Am Acad Dermatol. 2015 Mar 7].

Additional Pictures

Bullous Pemphigoid Bullous Pemphigoid

Rings may form.
Bullous Pemphigoid rings Bullous Pemphigoid rings

A tense bulla is typical
Bullous Pemphigoid

Hemorrhage into the bulla is not uncommon.
Bullous Pemphigoid

Bullous pemphigoid may initially present with diffuse urticarial lesions. Histology showing eosinophils is a clue. Direct immunoflourescence confirms the diagnosis.
Bullous Pemphigoid

Bullous Pemphigoid

Diffuse urticarial phase of bullous pemphigoid from nivolumab.
Bullous pemphigoid from Nivolumab Bullous pemphigoid from Nivolumab Bullous pemphigoid from Nivolumab Bullous pemphigoid from Nivolumab

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