Pemphigoid bullous L12.0

Authors: Prof. Dr. med. Peter Altmeyer, Maria Bostelmann

Co-Autors: Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 11.10.2021

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Synonym(s)

Agesemphigus; bullous pemphigoid; Bullous pemphigoid; dermatitis herpetiformis senilis; Erythema bullosum chronicum; Parapemphigus; Pemphigoid

History
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Lever, 1953

Definition
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Localized or exanthematic, blistering autoimmune disease of the skin and mucous membrane (mucosal infestation rather rare) of the elderly with subepidermal blistering.

Occurrence/Epidemiology
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Most frequent blistering autoimmune dermatosis. Incidence: 6-7/100.000 inhabitants/year. With increasing age, the incidence rises from about 10/100,000 inhabitants/year for 60-year-olds to over 40/100,000 inhabitants/year for 90-year-olds. There are indications that incidences have increased by a factor of 2-3 in the last 20 years.

Bullous pemphigoids are more frequently found in autoimmune diseases, e.g. polymyositis, ulcerative colitis, chronic polyarthritis (rheumatoid arthritis).

Etiopathogenesis
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The etiopathogenesis of the disease is unknown.

Bullous pemphigoid is a type II allergic reaction (cytotoxic reaction) according to the classification of Coombs and Gell. Formation of IgG autoantibodies (IgG1- and IgG4-Ak): Targets are hemidesmosomal antigens, bullous pemphigoid antigen 1 (BP230; bullous pemphigoid 230-kDa protein) and bullous pemphigoid antigen 2 (BP180; bullous pemphigoid 180-kDa protein= collagen type XVII). BP180, also known as type XVII collagen or BPAg2, is a transmembrane glycoprotein with a so-called type II orientation (the NH2 terminus is intracellular, the -COOH terminus is extracellular). Portions of the extracellular terminus (NC161 domain) act as immunodominant segments. BP230 (BPAg1) lies intracellularly and is part of the hemidesmonsomal plaque. Its carboxyl end binds to keratin filaments.

Apparently, IgE autoantibodies against the NC16A epitope of the BP 180 protein also play a pathogenetic role (these apparently only occur together with IgG-AK). The formation of the antigen-antibody complexes leads to complement-mediated chemotactic attraction of inflammatory cells or to the release of proteases. Serum levels of autoantibodies against the immunodominant NC16A domain of BP180 correlate with disease activity.

A special form of bullous pemphigoid appears to be anti-p200 pemphigoid.

More rarely, the disease occurs as a paraneoplastic syndrome (paraneoplastic bullous pemphigoid), e.g. in prostate carcinoma, rectal carcinoma, bronchial carcinoma (Giacaman A et al. 2018).

The following drugs and therapeutic procedures have been described as triggers of bullous pemphgoid:

Triggering by UV radiation (UVB, UVA/PUVA) PUVA therapy and X-rays is well documented.

Drug-induced BP shows great variability clinically. It may present as classic BP, exanthema exsudativum multiforme, or bullous drug exanthema. The skin lesions begin within weeks to months after the onset of drug use. Symptoms resolve after discontinuation of the drug. Serological and immunofluorescence microscopic findings are unchanged from classic BP.

Genetic predisposition to the disease is associated with the HLA-DQB1*0301 haplotype.

Of note is the observation that cerebral apoplexy increases the incidence of bullous pemphigoid (Braun-Falco M 2018)

Manifestation
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Occurs at an advanced age, usually after the beginning of the 6th decade. Rarely begins in childhood.

Localization
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Especially trunk, armpits, flexion sides of the upper arms, navel region, inner thighs. Less frequently, the palms of the hands/foot soles or the mucous membranes (DD. Pemphigus vulgaris) are involved.

Clinical features
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Frequent: Varied, colorful clinical picture with blistering on the flexor sides of the extremities and trunk and severe itching. The subepithelial, bulging blisters appearing in episodes do not develop on unmodified skin but on red, extensive erythema or urticarial plaques. They are often located at the edges. After bursting of the blisters erosions or crusts develop on erythematous skin. Healing without scarring or milia formation. In addition to healing blisters there are typically newly formed blisters; this results in a colourful juxtaposition of different stages of development of pemphigoid efflorescences.

The Nikolski phenomenon I is negative (important diagnostic phenomenon for the exclusion of pemphigus vulgaris).

The Nikolski phenomenon II (lateral shifting of already existing blisters) is positive, however, this phenomenon is very unspecific for bullous dermatoses.

Oral mucosal changes (rather rare but possible): Mostly no blisters detectable, so only sharply limited erosions (blisters burst quickly due to the high mechanical stress in the oral cavity). Low healing tendency of the erosions.

Rarely: In a few cases there is no formation of the clinically path-breaking blisters. Thus, the clinical leading symptom "bulging (firm) bladder" and the clear clinical assignment to the blister-forming diseases is not applicable. Instead, a clinical picture with severe, therapy-resistant itching, with extensive erythema or plaques, but also eczematous, urticaria or purigo-like skin changes is impressive.

Further special forms of the bullous pemphigoid:

  • Localized bullous pemphigoid (e.g. localized pretibial bullous pemphigoid)
  • Vegetative bullous pemphigoid
  • Cicatrising pemphigoid
  • Pemphigoid gestationis
  • IgA linear dermatosis
  • Pemphigoid non bullous
  • Seborrhoeic pemphigoid (mainly affects older women, localisationi front and back sweat gutter)
  • Dyshidrosiform bullous pemphigoid (picture of Dyshidrosis palmoplantaris, more rarely blisters on the rest of the body)
  • Vesicular bullous pemphigoid (reminiscent of dermatitis herpetiformis)
  • Bullous pemphigoid of childhood (often involvement of the palms of the hands and soles of the feet, also involvement of the oral mucosa)
  • Bullous pemphigoid under the image of a Prurigo simplex subacuta
  • Pemphigoid nodularis (besides blisters, occurrence of itchy nodules)
  • Erythrodermic bullous pemphigoid (very rare form that can occur after UV therapy)

Histology
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Histologically 2 variants of the bullous pemphigoid are distinguished:

  • Cell-rich variant: Subepidermal blister formation with pronounced inflammatory infiltration at the oedematous bladder floor and in the bladder lumen, consisting of numerous eosinophilic leukocytes, lymphocytes and neutrophilic leukocytes.
  • Low-cell variant: Subepidermal blister formation with intact papillae and little to no inflammatory infiltrate.

In biopsy of a pre-bladder stage (urticarial infiltrate), a focal, mixed-cell, epidermotropic infiltrate of lymphocytes, numerous eosinophilic and isolated neutrophil leukocytes is found in edematous papillary bodies and dilated blood and lymph vessels. A diagnostically valuable sign is the linear arrangement of leukocytes and also nuclear debris at the dermo-epidermal junctional zone. Eosinophilic subcorneal microabscesses are more rarely found.

Remark: For the technique of sampling see below. Pemphigus vulgaris.

Direct Immunofluorescence
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The diagnosis of bullous pemphigoid can be secured immunohistologically in connection with the clinical symptoms and the serological findings (this diagnosis is highly relevant!).

In perilesional skin, in decreasing frequency, detection of C3 (94% of patients), IgG (79%), IgM and IgA (each < 20%) linearly at the dermo-epidermal junction zone. Linear IgM detection at the basement membrane may be associated with macroglobulinemia.

A perilesional biopsy is important! The biopsy of a bladder can lead to a false positive (Ig and C3 is deposited non-specifically) or false negative result (Ig/C3 is proteolytically degraded or the bladder roof does not appear at all for technical reasons). A preference for a certain body region is diagnostically not recommended.

Indirect immunofluorescence
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Pemphigoid antibodies: circulating anti-basal membrane antibodies of the IgG class in 80-90% of patients. Here the most sensitive substrate is human split skin. By immunoprecipitation and immunoblotting the autoantibodies bind mainly to the autoantigens BP 180 and BP230. 125 kDa dermal protein requires further characterization.

In 5-10% of patients circulating IgA antibodies are found on the epidermal side.

In the so-called salt split skin examination there is a reaction of antibasal membrane antibodies with the epidermal part of the bladder (bladder cover).

The titers of indirect immunofluorescence do not correlate with the disease activity.

Differential diagnosis
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Pemphigus vulgaris, blistering dermatoses (Table 1).

General therapy
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The therapy must be based on various clinical criteria:
  • Age and underlying diseases (e.g. very old age, diabetes mellitus) of the patient.
  • Type and triggering of the pemphigoid (e.g. medication, UV-irradiation or paraneoplastic).
  • Acuteity and extent of the disease (generalized or localized, special form of scarring pemphigoid): In the case of questionable drug-induced bullous pemphigoid, the medication in question must be discontinued or converted. The neoplastic triggering is disputed, especially since the association with such tumours is described, which occur more frequently in the high pemphigoid age group per se.
  • Notice! "Small tumor search".

External therapy
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Local therapy should be symptomatic, e.g. with mild antiseptics such as 0.5-2% clioquinol cream(e.g. Linola-Sept, R049 ). Alternatively: cadexomeric iodine (Iodosorb ointment).

Alternative: 1% ethacridine lactate ointment.

The blisters are to be opened sterilely.

Internal therapy
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In general, with the exception of localized bullous pemphigoid, patients with bullous pemphigoid require internal glucocorticoids such as prednisolone (e.g. Decortin H) 80-100 mg/day initially combined with potent steroid-sparing immunosuppressants such as azathioprine (e.g. Imurek Filmtbl.) 100-150 mg/day.

In bullous pemphigoid of moderate (10-30% body surface area) to severe (>30% body surface area) severity, initial glucocorticoid doses are 1.5-2.0 mg/kg bw/day prednisone equivalent i.v. Several options are available as adjunctive immunosuppressants:

- Azathioprine is often still the first choice. Dosage: 1.5-2.0 mg/kg bw/day. Prior exclusion of thiopurine methyltransferase deficiency to avoid myelosuppression. Preventive gastric protection with an aluminium-containing antacid such as Magaldrate (e.g. Riopan 2-4 tbl. or 2-3 sachets). General guidelines for intensive care in severe cases are the same as for pemphigus vulgaris.

After stabilization of the condition, the glucocorticoid dose can be gradually reduced with unchanged azathioprine dosing. The glucocorticoid is applied perorally from a dose of < 50 mg prednisone equivalents (gastric protection with antacid) and reduced by 5 mg daily. The goal is a glucocorticoid dose at or below the Cushing threshold (for 16-alpha-methylprednisolone < 8 mg/day p.o.). Instead of non-halogenated prednisone/prednisolone, a chlorinated glucocorticoid can be used, e.g. cloprednol (Syntestane) at a continuous dose of 1.25-2.5 mg/day).

Follow-up: After 5-7 months, an attempt to discontinue immunosuppressive therapy can be made under close clinical supervision (first discontinue azathioprine, then the glucocorticoid). Re-initiate with intermediate immunosuppression at relapse (prednisone equivalent 0.5-1.0 mg/kg bw/day p.o. and azathioprine 1.0-1.5 mg/kg bw/day p.o.).

Other immunosuppressive options include:

- Dapsone (1.5mg/kg bw/d p.o. monotherapy or adjuvant to systemic glucocorticoids).

- Doxycycline (200mg/d p.o. monotherapy possibly in combination with nicotinamide (up to 2g/d) or adjuvant to systemic glucocorticoids)

- Methotrexate (up to 20mg s.c. per week, monotherapy or adjuvant to systemic glucocorticoids)

- Mycophenolate mofetil (Cellcept®, 2g/d p.o. , children 15-30mg/kg bw/d).

In case of resistance to therapy , alternative agents can be used:

  • - IVIG: Small studies have reported good experience with high-dose i.v. immunoglobulin therapy (e.g. Intratect as monotherapy). Dosage: 2.0 g/kg bw/day distributed over 3 days, monthly therapy cycles (high therapy costs!). According to our own experience, combinations with glucocorticoids or immunoadsorption are usually necessary.
  • - Immunoadsorption/Plasmapheresis.
  • - Anti-CD20 antibodies(Rituximab, monoclonal chimeric human-mouse antibody against the CD20 antigen, which is expressed by immature and mature B cells, but not by plasma cells).

Further, positive results have been described in the literature with:

Progression/forecast
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Chronic, intermittent course. Mortality without therapy is about 20%-40% (!) in the first year and is 2-3 times higher (mostly secondary infections) than in the comparable age group. Here, it is less the extent of the skin symptoms than the multimorbidity of the patients that is decisive.

Note(s)
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Associations with neurological diseases such as: dementia, Parkinson's disease, epilepsy, multiple sclerosis have been described (Kipsgaard L et al. 2017).

Literature
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  1. Kibsgaard L et al (2017) Increased frequency of multiple sclerosis among patients with bullous pemphigoid
    :a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid. Br J Dermatol 176:1486-1491.
  2. Balakirski G et al (2014) Bullous pemphigoid. Dermatologist 65: 1013-1016
  3. Brown Falco M (2018) Bullous pemphigoid triggered by stroke. Karger compass Dermatol 6:19-20
  4. Feliciani C et al (2015) Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol 172:867-877
  5. Ferreira C et al (2018) Bullous pemphigoid-like skin eruption during Treatment with Rivaroxaban: A Clinical Case Study. Eur J Case Rep Internal Med 5:000724.
  6. Fisler RE et al (2003) Childhood bullous pemphigoid: a clinicopathologic study and review of the literature. At J Dermatopathol 25: 183-189
  7. Giacaman A et al. (2018) Anular paraneoplastic bullous pemphigoid imitates linear IgA dermatosis in
    a 40-year-old patient.J Dtsch Dermatol Ges 16:481-483.
  8. Lever WF et al (1953) Pemphigus. Medicine 32: 2-123
  9. Powell AM et al (2002) Pemphigoid nodularis (non-bullous): a clinicopathological study of five cases. Br J Dermatol 147: 343-349
  10. Rose C et al (2007) Histopathology of anti-p200 pemphigoid. At J Dermatopaphol 29:119-124
  11. Sami N et al (2003) Influence of intravenous immunoglobulin therapy on autoantibody titres to BPAG1 and BPAG2 in patients with bullous pemphigoid. JEADV 17: 641-645
  12. Schmidt E et al (2000) New aspects on the pathogenesis of bullous pemphigoid. dermatologist 51: 637-645
  13. Schmidt E et al (2015) S2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. JDDG 13: 713-726
  14. Scholz J et al (2010) IgM-induced bullous pemphigoid in Waldenström's disease. JDDG 8: 952
  15. Schulze F et al. (2013) Bullous pemphigoid. Dermatologist 64: 931-945
  16. Wojnarowska F et al (2002) Guidelines for the management of bullous pemphigoid. Br J Dermatol 147: 214-221

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