Pemphigoid bullous L12.0

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

Clinical variants of bullous pemphigoid.

• Localized bullous pemphigoid (e.g., localized pretibial bullous pemphigoid).
• Vegetating bullous pemphigoid
• Non-bullous pemphigoid
• Juvenile pemphigoid
• Gestational pemphigoid (pregnancy pemphigoid)
• Seborrheic pemphigoid (mainly affects older women, localization = anterior and posterior sweat groove)
• Vesicular bullous pemphigoid (reminiscent of dermatitis herpetiformis)
• Dyshidrosiform bullous pemphigoid (picture of dyshidrosis palmoplantaris, rarely blisters on the rest of the body)
• Juvenile pemphigoid (bullous pemphigoid of childhood; frequent involvement of palms and soles, also oral mucosa involvement)
• Erythrodermic bullous pemphigoid (very rare form that can occur after UV therapy)
• Pemphigoid nodularis (besides blisters occurrence of itchy nodules)
• Bullous pemphigoid under the picture of prurigo simplex subactua
• Paraneoplastic bullous pemphigoid
• Drug-induced bullous pemphigoid

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).

The aetiopathogenesis of the disease is unknown.
Bullous pemphigoid is an autoimmune disease with the formation of mainly IgG (IgG1 and IgG4 subclasses) and (more rarely) IgE autoantibodies: the targets are hemidesmosomal antigens. The antibodies are directed against 2 antigens of the dermo-epidermal junction zone:

• bullous pemphigoid antigen 2 (BP180; bullous pemphigoid 180-kDa protein, also known as collagen type XVII (-s.a. COL17A1 gene) or BPAg2.
• Bullous pemphigoid antigen 1 (BP230; bullous pemphigoid 230-kDa protein, also known as BPAG1 or dystonin ).

The formation of the antigen-antibody complexes leads to complement-mediated chemotactic attraction of inflammatory cells or to the release of proteases and inflammatory blister formation, which begin within the ultrastructural lamina lucida.

The hemidesmosomal protein BP180 is considered to be the main autoantigen. It is a transmembrane glycoprotein with a so-called type II orientation (the NH2 terminus is intracellular, the -COOH terminus is extracellular). The parts of the extracellular terminus (NC161 domain) act as immunodominant sections. The serum level of autoantibodies against the immunodominant NC16A domain of BP180 correlates with the disease activity of the disease. Antibodies against BP 180 can be detected in around 90 % of BP patients.

BP230 (BPAg1) is located intracellularly and is part of the hemidesmonsomal plaque. Its carboxyl end binds to keratin filaments. IgG anti-BP230 antibodies are found in around 70 % of patients (Ishiura N et al. 2008). BP230 mediates the binding of keratin intermediate filaments to the hemidesmosomal plaque at the molecular level. The autoantibodies against BP230 can not only trigger inflammatory reactions in vivo, but also impair the structural stability of the hemidesmosomes (Shih YC et al. 2020). Consistent with this is the finding that a small subpopulation of BP patients selectively exhibit autoantibodies only against BP230 (Ramcke T et al. 2022). The importance of this antibody is also emphasized by the fact that IgG anti-BP230 antibodies tend to increase in proportion to the increase in disease duration.

IgE anti-BP180 antibodiesare found in around 30% of patients and IgE anti-BP230 antibodies in around 65% (Hashimoto T et al. 2017). The IgE anti-BP230 values show a strong association with the local accumulation of eosinophils (Ishiura N et al. 2008).

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 medications and therapeutic procedures are described as triggers of bullous pemphgoid, albeit less frequently than in pemphigus: ACE inhibitors (e.g. captopril, enalapril), amoxicillin, ampicillin, cephalexin, diazepam, DPP-4 inhibitors, etanercept, locally applied 5-fluorouracil, furosemide, anticoagulants (direct factor Xa inhibitors such as rivaroxaban), anticoagulants (direct factor Xa inhibitors such as rivaroxaban), anticoagulants (direct factor Xa inhibitors such as rivaroxaban).e.g. rivaroxaban), gold preparations, NSA (e.g. ibuprofen), penicillamine, penicillin V, salazosulfapyridine, sulfasalazine, sulfonamides and derivatives, terbinafine, photodynamic therapy, pembrolizumab. Drug-induced BP shows great clinical variability. It can appear as classic BP, as erythema multiforme or as bullous drug-induced exanthema. The skin changes begin within weeks to months after starting the medication. The symptoms subside after discontinuation of the medication. The serological and immunofluorescence microscopic findings are unchanged compared to classic BP.

Triggering by UV radiation (UVB, UVA/PUVA), PUVA therapy and X-rays is well documented and a genetic predisposition to the disease is associated with the haplotype HLA-DQB1*0301.

The observation that cerebral apoplexy increases the incidence of bullous pemphigoid is noteworthy (Braun-Falco M 2018). An analogous constellation was found for schizophrenia but not for anxiety disorders (Huang ICH et al. 2022).

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

V.a. trunk, armpits, flexor sides of the upper arms, umbilical region, inner thighs. More rarely, there is involvement of the palms/soles or mucous membranes (DD pemphigus vulgaris).

Frequent: Multifaceted, variegated clinical picture with blistering on the flexor sides of the extremities and trunk and intense pruritus. The subepithelial, turgid blisters, which occur in episodes, do not develop on unchanged skin but on red, extensive erythema or urticarial plaques. They are often localized at the edges. After the blisters burst, erosions or crusts develop on erythematous skin. Healing without scarring or milia formation. Newly formed blisters are typically found next to healing blisters; this results in a variegated coexistence of different stages of development of pemphigoid efflorescences.

Nikolski phenomenon I is negative (important diagnostic phenomenon to exclude pemphigus vulgaris).

In contrast, Nikolski phenomenon II (lateral displacement of preexisting blisters) is positive; however, this phenomenon is very nonspecific for bullous dermatoses.

Oral mucosal changes (rather rare but possible): Usually no blisters detectable but only sharply demarcated erosions (blisters burst rapidly due to the high mechanical stress in the oral cavity). Low healing tendency of the erosions.

Rare: In a few cases, the clinically groundbreaking blisters do not form. Thus, the clinical leading symptom "bulging (firm) blister" and the clear clinical assignment to the blister-forming diseases is omitted. Instead, a clinical picture with severe, therapy-resistant pruritus, with extensive erythema or plaque appears. However, eczematous, urticarial or Purigo-like skin changes may also occur.

Patients with bullous pemphigoid have an increased association with neurologic disorders, which may increase mortality. Neurologic disorders preceded bullous pemphigoid in the majority of cases with a median time interval of 6.7 years . Patients with BP had a significantly higher risk of apoplexy, dementia, epilepsy, multiple sclerosis, Parkinson's disease (Lai YC et al. 2016)

Histologically, 2 variants of bullous pemphigoid are distinguished:

• Cell-rich variant: Subepidermal blistering with marked inflammatory infiltrate at the edematous blister base and in the blister lumen, consisting of numerous eosinophilic leukocytes, lymphocytes, and neutrophilic leukocytes.
• Cell-poor variant: Subepidermal blister formation with intact papillae and little to no inflammatory infiltrate (it is conceivable that the blister contents in the noninflammatory variant are more like transudate than exudate).

Biopsy of a pre-blister stage (urticarial infiltrate), with edematous papillary body and dilated blood and lymphatic vessels, reveals a focal, mixed-cell, epidermotropic infiltrate of lymphocytes, numerous eosinophils, and scattered neutrophilic leukocytes. A diagnostically valuable sign is the linear arrangement of leukocytes and also nuclear debris at the dermo-epidermal junctional zone. Less frequently, eosinophilic subcorneal microabscesses are found.

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

The diagnosis of bullous pemphigoid can be confirmed immunohistologically in conjunction with the clinical manifestations and the serological findings (this diagnostic method is highly relevant!).

In perilesional skin, in descending frequency, detection of _C3 (94% of pat.), IgG (79%), IgM and IgA (each < 20%) linear at the dermoepidermal junction zone. Linear IgM detections at the basement membrane may be associated with macroglobulinemia.

Perilesional biopsy is important! Biopsy of a bladder may result in a false positive (Ig and C3 deposited nonspecifically) or a false negative finding (Ig/C3 proteolytically degraded, or the bladder roof does not present at all for technical reasons). A preference for a specific body region is not recommended diagnostically.

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.

Pemphigus vulgaris and other blistering dermatoses.

Erythema anulare centrifugum: Multiple, initially homogeneous 1.0-2.0 cm red plaques that heal centrally and expand centrifugally. Centrifugal growth of the plaques is several millimeters per day. This results in ring formations up to 6.0 cm in diameter within a few weeks. These may coalesce in multiple arches. Blistering is possible.

Typically, the plaques are smooth on the surface. In some cases, a fine lamellar scale ruff is found at the inner edge of the ring.

(Table 1).

Therapy must be based on various clinical criteria:

• Age and underlying diseases (e.g. very old age, diabetes mellitus) of the patient.
• Type and trigger of the pemphigoid (e.g. drug-induced, UV irradiation or paraneoplastic).
• Acuity and extent of the disease (generalized or localized, special form of scarring pemphigoid): In cases of questionably drug-induced bullous pemphigoid, discontinue or reposition the drugs in question. Neoplastic triggering is debatable, especially since the association with such tumors is described, which occur per se more frequently in the high pemphigoid age group.

Notice. "Tumor Search.

Local therapy should be symptomatic, e.g. with mild antiseptics such as 0.5-2% Clioquinol cream(e.g. Linola-Sept, Clioquinol cream 0.5-2%).

Alternative: Cadexomer iodine (Iodosorb ointment).

Alternative: 1% ethacridine lactate ointment.

The blisters should be opened sterilely.

Note: a randomized study showed that with the large-area external application of clobetasoplpropionate in cream form, (40g/day for 14 days, then gradual reduction) the same positive effects can be achieved as with a systemic applikaiton of prednisolone (0.5mg/kgKg). However, it can be assumed that systemic effects of this highly potent steroid have occurred (Joly P et al. 2002).

Basically, 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% KOF) severity, initial doses of glucocorticoid are 1.5-2.0 mg/kg bw/day prednisone equivalent i.v. As an adjunctive immunosuppressant, several options are possible:

• Azathioprine is often still agent of 1st choice. Dosage depending on TMP activity: 0.5-2.5 mg/kg bw/day. Preventive gastric protection with an aluminum-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 starting at 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 may be used, e.g., cloprednol (Syntestane) at a continuous dose of 1.25-2.5 mg/day).

Onward course:

After 5-7 months, a discontinuation of immunosuppressive therapy can be attempted under close clinical monitoring (first discontinue immunosuppressive agent e.g. azathioprine, then gradually, if recurrence continues to be free, discontinue glucocorticoid).

Re-enter with intermediate immunosuppressionif recurrence occurs (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 evnt. 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!). In our own experience, combinations with glucocorticoids or immunoadsorption are usually necessary.
• - Immunoadsorption/Plasmapheresis.
• - Anti-CD20 antibody(Rituximab, monoclonal chimeric human-mouse antibody against the CD20 antigen expressed by immature and mature B cells, but not by plasma cells).

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

• - Cyclophosphamide (2mg/kg bw/d p.o. )
• - Anti-IgE antibody(Omalizumab)

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.

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

Type XVII collagen is encoded by the COL17A1 gene. Unlike most collagens, collagen XVII is a transmembrane protein, a structural component of hemidesmosomes and multiprotein complexes at the dermal-epidermal basement membrane zone that mediate keratinocyte adhesion to the underlying membrane.

Diseases associated with the COL17A1 gene include:

• Epithelial recurrent erosive dystrophy, a very rare congenital form of superficial corneal dystrophy.

and

• Epidermolysis bullosa junctionalis generalized intermediate (non-Herlitz).

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