Editors

AlexanderSalava

Chronic Bullous Diseases (Dermatitis Herpetiformis, Pemphigoid, Pemphigus)

Essentials

Bullous autoimmune skin diseases may be suspected based on the clinical picture.
The diagnosis is usually confirmed in specialized care by antibody tests and examinations such as direct immunofluorescence of a skin biopsy sample.
Treatment is started in specialized care, but during times of remission, patients can be followed up in primary health care.

General information

Bullous autoimmune diseases are a group of uncommon skin diseases distinguished by their clinical picture, serum antibodies and the result of immunofluorescence of a skin biopsy sample.
Autoantibodies are produced against skin structures, causing an immune response and the visible symptoms.
The clinical picture depends largely on what skin structures the response affects (structures most commonly situated in the basement membrane and dermoepidermal junction).
Blisters form when more superficial skin structures are detached from deeper structures, with a blister forming between them (e.g. the basement membrane being detached from the underlying tissue).
It is important for general practitioners to consider a bullous autoimmune skin disease based on the clinical picture and the symptoms and to refer the patient to specialized care.

Common or other possible causes for vesicles on skin

Eczematous diseases (such as acute allergic contact eczema Allergic Contact Dermatitis, vesicular hand eczema Hand Dermatitis, pompholyx)
Viral infections (herpes simplex Herpes Simplex Infection of the Skin, shingles Shingles (Herpes Zoster))
Bacterial infections (bullous impetigo Impetigo, erysipelas Erysipelas)
Ringworm (such as bullous tinea pedis, id reactions) Dermatomycoses
Oedema (such as leg oedema, acute heart failure) Leg Oedema
Mechanical irritation (traction vesicles)
Diabetes (diabetic blisters distally on the limbs)
Photodermatitis (sunburn, phytophotodermatitis) Photodermatitis
Insect bites and stings Insect Stings and Bites
Erythema multiforme Erythema Multiforme
Drug reactions (fixed drug reaction, Stevens-Johnson syndrome) Hypersensitivity to Drugs

Dermatitis herpetiformis

See also article on Coeliac disease Coeliac Disease.

General remarks

Cutaneous manifestation of coeliac disease seen in about 10% of patients with coeliac disease
Onset most often in adulthood.
There are genetic predisposing factors (such as HLA-DQ2 and -DQ8). About 15% of patients with dermatitis herpetiformis have been found to have close relatives with intestinal coeliac disease or dermatitis herpetiformis.
Dietary gluten induces formation of IgA antibodies to epidermal structures. The most common dermal antigen is transglutaminase 3 (TG3). In intestinal coeliac disease, the most common antigen is typically transglutaminase 2 (TG2).
The disease usually involves coeliac disease-type damage to the small intestine, even though this is milder than in intestinal coeliac disease. The intestinal symptoms may be only minor.
The prevalence of other autoimmune diseases (such as hypothyroidism, vitiligo) is increased.

Clinical features

There is an extremely itchy rash, typically on extensor surfaces of the lower arms, and knees and on the buttocks.
Other relatively typical sites include the scalp, upper and lower back and the face.
There may be small vesicles (picture F1) on erythematous skin, and scratches (pictures F2 F3).
However, in many cases there are no vesicles but just small itchy papules, sores of blisters (erosion), scabs or just patchy hyperpigmentation.
Significant questions
- Have near relatives had coeliac disease?
- Has the patient been diagnosed with any autoimmune disease?
- Are there abdominal symptoms, weight loss or anaemia?

Diagnosis

The suspicion will arise based on the clinical picture.
It may be difficult to distinguish dermatitis herpetiformis from other itchy skin diseases; typical sites and symmetricity of the rash are essential.
To confirm the diagnosis, direct immunofluorescence of a skin biopsy sample is needed (granular deposition of IgA in the papillary dermis).
This is a fresh frozen tissue sample taken from healthy skin close to the rash (such as the medial lower arm or buttocks). A fresh sample is normally taken in specialized care.
Ordinary histopathology is unspecific.
It is also important to firstly determine the transglutaminase (TG2) antibodies in coeliac disease (IgA); see Coeliac disease Coeliac Disease.
However, as about one in three patients with dermatitis herpetiformis has negative TG2 antibodies, being seronegative will not exclude dermatitis herpetiformis.

Differential diagnosis

Atopic eczema Atopic Eczema (Atopic Dermatitis) in Adults Atopic Dermatitis in Children: Clinical Picture, Diagnosis and Treatment (may appear as papular rash on elbows and knees particularly in children and adolescents [juvenile papular dermatosis]).
Nummular eczema (an eczematous disease with patches at various typical sites) Nummular Dermatitis
Scabies (acute, itchy rash, often papular) Scabies
Insect bites (e.g. bedbug, fleas) Insect Stings and Bites
Nodular prurigo (prurigo nodularis)
Other rare bullous autoimmune skin diseases (e.g. diseases of the pemphigoid group, such as bullous pemphigoid or linear IgA disease)

Treatment

The most important treatment is a gluten-free diet for life.
The long-term prognosis is good if dietary treatment is appropriate.
Guidance and consultation provided by a therapeutic dietitian is essential.
People with coeliac disease may be eligible for various social benefits. Check local policies.
Dietary treatment usually eliminates the symptoms, improves quality of life and prevents complications of dermatitis herpetiformis, such as intestinal lymphomas.
As dietary treatment often alleviates skin symptoms slowly, dapsone can be started in specialized care for patients with severe symptoms.
- Dapsone relieves skin symptoms very quickly but as its use is associated with effects such as changes to the blood count or haemolytic anaemia, regular laboratory tests (such as basic blood count with platelet count, creatinine, ALT) and clinical follow-up are absolutely necessary.
- Medication can often be withdrawn after a few years (as long as dietary treatment continues).
Topical glucocorticoids may alleviate skin symptoms (moderately potent or potent glucocorticoid ointments in courses of 2-4 weeks, for example).
In dermatitis herpetiformis, healing of the rash and normalization of anti-transglutaminase antibodies (IgA; if these were elevated at first) are sufficient signs of successful treatment.

Indications for specialist consultation

Investigations and treatment should be initiated by a dermatologist.
An internist or a gastroenterologist can be consulted, as necessary (in the case of refractory intestinal symptoms, for example). Routine endoscopy is not recommended.
In the stable phase, a general practitioner can be responsible for follow-up.
- During follow-up, clinical symptoms should be assessed and anti-transglutaminase antibodies (IgA) determined every 2-3 years, for example.

Pemphigoid (bullous pemphigoid)

General remarks

A rare bullous autoimmune disease with increased prevalence, typically occurring in the elderly
Often develops without any particular triggering factor. Some patients have a history of skin injury (such as a burn) or strong UV exposure.
Neurological diseases (such as Alzheimer's or Parkinson's disease) and use of certain medicines (such as antidiabetic medication of the gliptin group) 1-6 months previously are more common than in the reference population and may predispose the patient to developing the disease.
Autoantibodies attack the junction between the lowest epidermal keratinocyte layer and the basement membrane, detaching these from each other (type XVII collagen, a structural component of hemidesmosome, pemphigoid antigen 180, BP180).

Symptoms

Pemphigoid mainly affects elderly people (> 60 years of age). If an elderly person has itchy skin, pemphigoid should be suspected.
Rash may be preceded by itching, which may be the only symptom for a long time.
Pemphigoid does not cause fever or systemic symptoms but it may affect the general condition of elderly patients in particular indirectly through itching and sleeping problems.
Rash typically occurs on the trunk, in proximal parts of the limbs and in flexural areas.
Typically large, rather thick-walled, translucent, and itchy vesicles (i.e. bullae) develop on erythematous skin on the trunk or on proximal parts of the limbs (pictures F4 F5).
As the vesicles or bullae heal, weeping bases (erosion) and erythematous patches remain. Milia or post-inflammatory hyperpigmentation may be seen.
Before and in addition to typical bullous dermatosis, there may be just erythematous plaques or patches resembling eczema. The clinical picture may thus imitate other diseases, such as urticaria Hives (Urticaria) or eczematous diseases.
Mucosal symptoms occur in about 10-20% of patients, most often on the oral mucosa (ulcers, erosions). There is also a form of disease restricted to the mucosa (mucous membrane pemphigoid; picture F6) Oral Blistering Diseases.

Diagnosis

The typical patient is an elderly person with itching of unclear origin.
Early pemphigoid in particular may be difficult to distinguish from other pruritic skin diseases. Widespread clear vesicles refractory to ordinary treatments are typical.
The diagnosis is based on the clinical picture, positive antibodies and direct immunofluorescence of a sample taken from an area close to the rash (deposition of IgG or complement C3 in a linear pattern on the basement membrane at the dermoepidermal junction).
Indirect immunofluorescence examination of anti-basement membrane antibodies in the skin epithelium is unspecific and not necessary to diagnose pemphigoid.
Ordinary histopathological examination can show subepidermal blister formation suggesting this diagnosis.
In differential diagnosis, it may also be necessary in individual cases to determine also other skin autoantibodies.
Slightly elevated anti-BP180 antibody levels can be found in some patients with pruritic skin diseases and in elderly people in the absence of pemphigoid.

Differential diagnosis

Eczematous diseases (may be bullous at the acute stage)
Urticaria (does not cause blisters; there are migratory skin lesions) Hives (Urticaria)
Impetigo (may be bullous; itching is usually insignificant) Impetigo
Drug reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (acute disease, association with drugs, malaise) Hypersensitivity to Drugs
Scabies (may involve blisters, particularly on hands and feet) Scabies
Rarer diseases of the pemphigoid group (such as mucous membrane pemphigoid, gestational pemphigoid or linear IgA disease)
Other rare bullous autoimmune skin diseases (such as dermatitis herpetiformis, the pemphigus group of diseases, epidermolysis bullosa acquisita)

Treatment Interventions for Mucous Membrane Pemphigoid and Epidermolysis Bullosa Acquisita, Interventions for Bullous Pemphigoid

Treatment should be guided by specialized care, and it must be based on individual assessment (feasibility of treatment, the patient's risk factors, any benefits or harms).
The primary aim is to eliminate itching, to decrease skin symptoms and to improve the patients' quality of life.
In milder cases, topical treatment alone may be used as far as feasible.
- Intermittent treatment of areas with rash and sores of blisters with potent or very potent glucocorticoid ointment in courses of 3-4 weeks, for example.
- A very potent glucocorticoid ointment is used initially for many patients extensively on all areas with rash in a longer course according to a separate regimen (transcutaneous glucocorticoid treatment).
  - Clobetasol ointment, 30 g/day for 1 month followed by 30 g/day every second day for 1 month, followed by 30 g/day twice a week for 1 month and then 30 g/day once a week, as necessary
  - Potent topical glucocorticoid therapy is used to try to decrease the need for systemic glucocorticoid treatment with the adverse effects involved.
- In milder cases, doxycycline 100 mg twice daily (combined with topical treatments) may also be effective. For the first few months, doxycycline can be combined with a systemic glucocorticoid as necessary.
In more severe cases, the primary treatment is an oral glucocorticoid. The initial dose should be determined individually depending on the severity of the clinical picture and the patient's risk factors; for example, prednisolone 0.5(-1.0) mg/kg/day.
- The dose should be decreased according to response, aiming at the lowest possible dose that keeps symptoms under control. The typical period of treatment is 6-12 months. Many patients need long-term treatment with low maintenance doses.
- Adverse effects of long-term glucocorticoid treatment must be considered; they are particularly significant in elderly patients Pharmacological Glucocorticoid Treatment.
- In severe forms of disease and those responding poorly to glucocorticoid therapy, immunosuppressive medication (such as azathioprine or methotrexate) has been used in addition to glucocorticoid therapy.
Bursting vesicles or bullae (with a needle, for example) is often useful. Suitable paraffin dressings and compresses can be used for erosive surfaces.
Response to treatment can be assessed based on clinical symptoms. In addition, anti-BP180 antibodies can be used to assess disease activity; their levels decrease during good response to treatment and remission.
The course of the disease is chronic. Relapses may occur during or after treatment.

Indications for specialist consultation

Confirmation of the diagnosis and differential diagnosis (immunohistology) are the tasks of a specialist. The patient should be referred without delay.
The treatment is best started by a specialist. Often the disease continuously behaves in the same manner in the same patient.
A dermatologist should be consulted to confirm the diagnosis (immunohistology) and to plan treatment.
In the stable phase, a general practitioner can be responsible for follow-up (consulting specialized care, as necessary).
After a treatment regime has been found that is the least demanding for the patient (topical treatment, in particular), it can be repeated under the management of a general practitioner if the disease recurs.

Pemphigus

A group of rare bullous autoimmune diseases, their clinical picture varying depending on the structures affected by autoantibodies.
The antibodies typically affect junctions between epidermal cells (desmosomes).
In pemphigus vulgaris, the most important autoantigen is desmoglein 3, which explains the more severe symptoms on the mucosa.
In pemphigus foliaceus, the main antigen is desmoglein 1, and the disease therefore usually only occurs on the skin.

Symptoms

Pemphigus vulgaris
- Patients are typically middle-aged.
- The disease usually begins with mucosal (particularly oral) ulcers and erosion.
- Later on, extensive blistering and erythematous erosive surfaces may develop on the skin.
- In the subtype pemphigus vegetans, there are ulcers and erythematous nodules resembling cauliflower in flexural areas.
Pemphigus foliaceus
- Onset usually in adulthood
- There are symptoms primarily on the skin.
- The blisters are superficial and leave erythematous, scaly patches after bursting.
- Clinically, the disease may resemble eczematous diseases or psoriasis.
- There are symptoms mostly on the head and the upper body.
- In the subtype pemphigus erythematosus, symptoms are aggravated by UV exposure, and patients have positive antinuclear antibodies. Clinically, the disease resembles subacute cutaneous lupus erythematosus (SCLE) Systemic Lupus Erythematosus (Sle).

Diagnosis

The diagnosis is based on the clinical picture, positive antibodies (serum Dsg1 and Dsg3; a combination test is available) and direct immunofluorescence of a sample taken from an area close to the rash (reticular deposition of IgG and complement C3 between epidermal keratinocytes).
Indirect immunofluorescence of epidermal intercellular material is unspecific but suggestive of the diagnosis.
Ordinary histopathological study can show intraepidermal blister formation suggesting this diagnosis.
In differential diagnosis, it may also be necessary in individual cases to determine other skin autoantibodies.
Anti-desmoglein antibodies usually reflect disease activity, and they are also used for follow-up.
Differential diagnosis is similar to that for bullous pemphigoid.

Treatment

Treatment and follow-up are usually carried out in specialized care. The treatment strategy should be planned according to the subtype of disease and to the patient profile. Treatment is usually started with high-dose systemic glucocorticoids (such as prednisolone 1[-2] mg/kg/day) and adjuvant medication (such as azathioprine or methotrexate) to reduce the dose of glucocorticoid required.
Glucocorticoid doses are reduced slowly depending on the clinical response and decreasing antibody levels.
There is significant variation by patient and disease subtype in response to treatment, in what glucocorticoid dose is sufficient and in the need for adjuvant therapy.
Intravenous rituximab is effective in more severe or refractory cases.
Treatment is usually needed for a long time - several years - and its long-term and adverse effects should be monitored Pharmacological Glucocorticoid Treatment.
Suitable paraffin dressings and compresses can be used for erosive surfaces remaining after vesicles or blisters.
Potent or very potent glucocorticoid ointments are applied topically to the skin in courses of 3-4 weeks, for example.
The oral mucosa can be treated with glucocorticoid mouthwash (such as extemporaneously prescribed triamcinolone solution or an extemporaneously prescribed gel with 4 ingredients: a corticosteroid ointment, lidocaine-adrenalin gel, chlorhexidine gel and nystatin solution) or potent glucocorticoid ointments in courses of 3-4 weeks, for example. Topical analgesic gels may also help.
The course of the disease is chronic. Relapses may occur during or after treatment.

Indications for specialist consultation

The diagnosis is normally confirmed (immunohistology) and treatment and follow-up are carried out in specialized care.

References

Jiirasutat N, Pongchareon P, Weschawalit S. Bullous pemphigoid and diabetes mellitus: a systematic review and meta-analysis. Int J Dermatol 2024;63(5):572-579 [PubMed]
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Rodriguez R, Sivesind TE, Murrell D, et al. From the Cochrane Library: Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus. JMIR Dermatol 2023;6():e46812 [PubMed]
Borradori L, Van Beek N, Feliciani C, et al. Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol 2022;36(10):1689-1704 [PubMed]
Kaunisto H, Salmi T, Lindfors K, et al. Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis: Lessons from Celiac Disease. Int J Mol Sci 2022;23(6): [PubMed]
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Görög A, Antiga E, Caproni M, et al. S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol 2021;35(6):1251-1277 [PubMed]
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[Coeliac disease]. A Current Care Guideline. Working group appointed by the Finnish Medical Society Duodecim and Finnish Society of Gastroenterology. Helsinki: Finnish Medical Society Duodecim, 2018 (accessed 11 Oct 2024). Available in Finnish at http://www.kaypahoito.fi/hoi08001.