In Germany, more than 2000 new patients per year have been calculated to be diagnosed with autoimmune blistering diseases. In a recent survey, the most frequently applied treatment regimens for bullous pemphigoid were class IV topical corticosteroids and oral prednisolone 0.5 mg or 1.0 mg/kg/d plus dapsone or azathioprine. For pemphigus, two-thirds of the clinics applied oral prednisolone at doses of 1.0 mg or 1.5 mg/kg/d and in more than 80% of departments, azathioprine was chosen as concomitant immunosuppressant. High-dose intravenous immunoglobulin, rituximab, and immunoadsorption are increasingly used for refractory patients. Treatment and diagnostic costs are covered by the health insurances when applied according to published expert recommendations.
In Germany, 5250 fully trained dermatologists were registered at the end of 2009, including 900 working in hospitals and 4000 in outpatient clinics and private practices (statistics of the German Medical Association; www.bundesaerztekammer.de ). Almost all patients with autoimmune bullous disease are initially referred to dermatology departments at university or nonuniversity hospitals for diagnosis and treatment decisions. Most patients are initially treated as inpatients and then allocated to specialized outpatient departments of the hospital or private practices according to the patients’ preferences.
At the University of Lübeck and the University of Kiel, specialized interdisciplinary outpatient departments for the treatment of patients with immunobullous diseases have been established in Comprehensive Centers for Inflammation Medicine. In these centers, patients with inflammatory diseases are managed in interdisciplinary teams, including interdisciplinary outpatient clinics and weekly case conferences. This approach facilitates clinical studies, data collection, and biobanking.
Health insurance is compulsory in Germany. It covers all costs for treatment regimens that have been licensed for a particular disease. In addition, for life-threatening diseases, off-label treatments that have been shown to be beneficial are covered.
Epidemiology
The incidence of pemphigus was calculated to be 2.3 new cases per million per year in Germany. With a population of 82.14 million, including 15.57 million inhabitants with a migration background at the end of 2008 (Federal Institute of Statistics, www.destatis.de ), about 200 newly diagnosed patients with pemphigus per year are expected in Germany. The age-adjusted incidence of pemphigus vulgaris was 9-fold higher in patients with a migration background compared with native Germans. The incidence of bullous pemphigoid (BP), by far the most frequent autoimmune blistering disease, has been determined to be 13.4 per million per year in a recent prospective study in 2001 and 2002 in Lower Franconia, a well-defined region in southern Germany, followed by pemphigoid gestationis (2.0 per million per year) and mucous membrane pemphigoid (2.0 per million per year). Based on these data, in 2002, a total of 1830 new patients with immunobullous disorders were estimated. The incidence of BP in Germany has doubled within the last 10 years, an observation that may be related to the increasing age of the general population and advances in the diagnostic tools. Because the incidence of BP dramatically increases with age resulting in an incidence of 150 to 190 per million per year for patients who are 80 years and older, in 2010, at least 3450 new patients with autoimmune blistering diseases can be expected to be diagnosed in Germany.
Survey among secondary and tertiary referral centers for autoimmune bullous diseases
A standardized questionnaire was sent to all 34 university departments and 38 nonuniversity hospitals with inpatient dermatology departments. The questionnaire consisted of 4 questions about the diagnostic procedures for immunobullous disorders performed in the departments: (1) direct immunofluorescence (IF) microscopy; (2) indirect IF microscopy on monkey esophagus, guinea pig esophagus, human salt-split skin, monkey bladder, rat bladder, and complement binding test on human salt-split skin; (3) commercially available enzyme-linked immunosorbent assay (ELISA) systems, including BP180 NC16A, BP230, desmoglein 1, desmoglein 3, and envoplakin; and (4) in-house ELISA systems and immunoblotting analyses for the detection of autoantibodies against BP180, BP230, laminin 332, type VII collagen, p200 protein, α6 integrin, β4 integrin, desmoplakin I/II, periplakin, and envoplakin. For each test system, the answer yes or no could be marked.
In the treatment section of the questionnaire, first-line therapies for pemphigus vulgaris/foliaceus and BP were requested. In addition to the most frequent therapeutic regimens that could be marked with a cross, other options could be added as free text.
All 34 university departments and 30 of 38 (79%) nonuniversity hospitals with inpatient care for patients with dermatologic problems completed the questionnaire, resulting in a total response rate of 89%.
Survey among secondary and tertiary referral centers for autoimmune bullous diseases
A standardized questionnaire was sent to all 34 university departments and 38 nonuniversity hospitals with inpatient dermatology departments. The questionnaire consisted of 4 questions about the diagnostic procedures for immunobullous disorders performed in the departments: (1) direct immunofluorescence (IF) microscopy; (2) indirect IF microscopy on monkey esophagus, guinea pig esophagus, human salt-split skin, monkey bladder, rat bladder, and complement binding test on human salt-split skin; (3) commercially available enzyme-linked immunosorbent assay (ELISA) systems, including BP180 NC16A, BP230, desmoglein 1, desmoglein 3, and envoplakin; and (4) in-house ELISA systems and immunoblotting analyses for the detection of autoantibodies against BP180, BP230, laminin 332, type VII collagen, p200 protein, α6 integrin, β4 integrin, desmoplakin I/II, periplakin, and envoplakin. For each test system, the answer yes or no could be marked.
In the treatment section of the questionnaire, first-line therapies for pemphigus vulgaris/foliaceus and BP were requested. In addition to the most frequent therapeutic regimens that could be marked with a cross, other options could be added as free text.
All 34 university departments and 30 of 38 (79%) nonuniversity hospitals with inpatient care for patients with dermatologic problems completed the questionnaire, resulting in a total response rate of 89%.
Diagnosis
All university and 93% nonuniversity departments performed direct IF microscopy. Indirect IF microscopy on monkey/guinea pig esophagus and human salt-split skin was done in 76% and 68% of university departments and 50% and 23% nonuniversity departments, respectively. Commercial ELISA systems for antidesmoglein and anti-BP180 antibodies were applied in 65% and 76% of university departments and 30% and 37% of nonuniversity departments, respectively. Noncommercial assays for the detection of autoantibodies in immunobullous diseases were used in 19% of dermatology departments, including 21% of university departments and 17% of nonuniversity departments. In addition, in 27% of departments, sera were sent for evaluation to external laboratories, including both university departments of dermatology and private laboratories.
This is the first survey on the diagnostic methods for immunobullous diseases in Germany. This survey reveals that direct IF microscopy is within the standard diagnostic repertoire in almost all dermatologic departments. Detection of serum antibodies by indirect IF microscopy and commercial ELISA systems is also widespread, whereas more sophisticated noncommercial systems are only used in a few specialized departments. A more detailed analysis of the diagnostic standard for immunobullous disorders in Germany is in preparation.
The diagnostic pathway for immunobullous dermatoses at the Department of Dermatology in Lübeck is summarized in Fig. 1 along with recent reviews. Diagnostic criteria used in the authors’ department are detailed in Table 1 .
| Diagnosis | Criteria | |||
|---|---|---|---|---|
| Clinic | Direct IF Microscopy a | Indirect IF Microscopy | ELISA/Immunoblotting | |
| Bullous pemphigoid | Blisters/erosions not predominantly on mucous membranes | IgG>IgA and/or C3 along the BMZ | IgG>IgA at the blister roof b | IgG reactivity with BP180 |
| Pemphigoid gestationis | Pregnancy, pruritic skin lesions | IgG and/or C3 along the BMZ | C3 at the blister roof c | IgG reactivity with BP180 |
| Mucous membrane pemphigoid d | Blisters/erosions not predominantly on mucous membranes | IgG and/or IgA and/or C3 along the BMZ | IgG and/or IgA and/or C3 at the blister roof b | IgG and/or IgA reactivity with BP180, laminin 332, or α 6 β 4 integrin |
| Linear IgA disease | Blisters/erosions not predominantly on mucous membranes | IgA>IgG along the BMZ | IgA>IgG at the blister roof b | IgA reactivity with BP180 |
| Dermatitis herpetiformis | Urticarial plaques or vesicles | Granular IgA in dermal papillae | IgA at the endomysium e | IgA reactivity with epidermal and/or tissue transglutaminase and/or deamidated gliadin |
| Epidermolysis bullosa acquisita | Blisters/erosions not predominantly on mucous membranes | IgG and/or IgA and/or C3 along the BMZ | IgG and/or IgA on the blister floor b | IgG and/or IgA reactivity with type VII collagen |
| Anti-p200/laminin γ 1 pemphigoid | Blisters/erosions not predominantly on mucous membranes | IgG and/or C3 along the BMZ | IgG at the blister floor b | IgG reactivity with a 200 kDa protein in dermal extract and/or laminin γ 1 |
| Lichen planus pemphigoides | Blisters/erosions and lichenoid papules | IgG and/or C3 along the BMZ | IgG at the blister roof b | IgG reactivity with BP180 NC16A |
| Pemphigus vulgaris | Blisters/erosions on mucous membranes | Intercellular IgG and/or C3 deposits in the epidermis/epithelium | Intercellular IgG deposits in the epithelium e | IgG reactivity with desmoglein 3 |
| Pemphigus foliaceus | Blisters/erosions on the skin | Intercellular IgG and/or C3 deposits in the epidermis | Intercellular IgG deposits in the epithelium e | IgG reactivity with desmoglein 1 |
| IgA pemphigus | Blisters/erosions/pustules on the skin | Intercellular IgA deposits in the epidermis | Intercellular IgA deposits in the epithelium e | IgA reactivity with desmocollins or desmoglein 3 |
| Paraneoplastic pemphigus f | Blisters/erosions on mucous membranes and the presence of a neoplasm | Intercellular IgG and/or C3 deposits in the epidermis/epithelium | Intercellular IgG deposits in the epithelium e and IgG in urothelium g | IgG reactivity against plakins and/or desmoglein 3 or 1 f |
Related posts:
Autoimmune Blistering Diseases Part II—Diagnosis and Management
Rituximab and its Use in Autoimmune Bullous Disorders
Evidence-Based Management of Bullous Pemphigoid
Pemphigoid Gestationis: Current Management
The International Pemphigus and Pemphigoid Foundation
Treatment of Chronic Bullous Disease of Childhood
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