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Prevalence and age distribution of pemphigus and pemphigoid diseases among paediatric patients in Germany – Hübner – – Journal of the European Academy of Dermatology and Venereology

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Introduction

Autoimmune bullous diseases (AIBD) comprise about a dozen entities characterized by autoantibodies against structural proteins of the dermal–epidermal junction (pemphigoid diseases) and the epidermis/epithelium (pemphigus diseases), resulting in sub‐ or intradermal blistering and erosions of the skin and/or mucous membranes (Table 1).1, 2 While most of these diseases occur in adults, children affected by AIBD are rare.3-6

Table 1.
Autoimmune bullous diseases in children, their target antigens and typical clinical presentation
Disease Target antigen Clinical features
Pemphigus vulgaris

Desmoglein 3

Desmoglein 1

Flaccid blisters, erosions and crusts on the skin, painful erosions at the mucous membranes
Pemphigus foliaceus

Desmoglein 1 Only skin affected with scaly and crusted erosions, often pruritus
Bullous pemphigoid

BP180

BP230

Tense blisters, erosions and crusts, severe pruritus, mucous membranes rarely affected
Linear IgA dermatosis

Soluble ectodomain of BP180 (LAD‐1)

BP230

Erythema, tense blisters and vesicles in a typical arrangement (‘crown of jewels’), mucosal involvement possible
Mucous membrane pemphigoid

Soluble ectodomain of BP180 (LAD‐1)

BP180

BP230

Laminin 332

Only or predominantly mucous membranes affected with blisters and erosions, scarring of conjunctiva
Epidermolysis bullosa acquisita

Type VII collagen

Mechanobullous type: blisters, erosions, crusts and scars in exposed sites (Fig. 1)

Inflammatory type: like BP or LAD

  • BP, bullous pemphigoid; LAD, linear IgA disease.


  • Also termed chronic bullous dermatosis of childhood.

image

Erosions on the buccal mucosa (a) and erythema, crusts and a tense blister on the toes of the left foot in a 5‐year old boy with epidermolysis bullosa acquisita (b).

Prognosis of AIBD in minors is usually better compared to adults. However, in minors, these diseases usually also require longer immunosuppression with potent topical and oral corticosteroids as well as immunosuppressants and – modulants.7, 8 Clinical trials in children with AIBD are lacking.

Only a few studies on incidences of AIBD in Europe are available.9, 10 Most reports focus on the most frequent AIBD, bullous pemphigoid and on pemphigus. Incidence of bullous pemphigoid in Europe ranges from 10 to 25 patients/million/year.10-13

Registry data from the UK and Sweden revealed incidences for bullous pemphigoid of about 70/million/year.14, 15 Incidences of pemphigus in Europe are lower, ranging from 0.8 in Finland and Germany to 6.8/million/year in the UK.16

Prevalence of AIBD were estimated to be 0.05% in Germany in 2014, resulting in about 40 400 patients.17 In contrast, epidemiological data about AIBD in children are rare. Linear IgA disease, also termed chronic bullous dermatosis of childhood, is regarded as the most frequent AIBD in children.4, 5 Systemic data about the prevalence of AIBD in minors have not been reported so far.

The aim of this study was therefore to determine the prevalence of AIBD in children in Germany and to analyse the sex and age distribution within this population.

Patients and methods

The current dataset is derived from the Techniker Krankenkasse, the largest German health insurance that insured about 9.7 million individuals representing about 12% of the German general population, including 1 715 882 below the age of 18 years representing 12.8% of the population below 18 years of age in 2015. Diagnoses were based on the ICD‐10‐GM classification for the year 2015. When one patient had more than one entry for 2015, both codes were kept. Two patients had two ICD‐10 codes for AIBD. In one patient (L12.1 and L12.0), we classified her as L12.0 because of the higher probability to suffer from bullous pemphigoid rather than mucous membrane pemphigoid. In the other patient, 12.1 and 12.9 were coded and she was classified with the specific code L12.1.

To control for a slightly different demographical composition of the insured children compared with the general German population regarding age and sex, data were adjusted to the general German population based on the data of the Federal Statistical Office of Germany for the years 1998 to 2015. We have previously applied a similar approach to estimate the prevalence of AIBD in patients of all ages.17

Results

Prevalence

Among 1 715 882 million insured individuals below the age of 18 years, 174 children were identified to have an AIBD ICD‐10 code resulting in an adjusted prevalence of 101.1/million minors (95% lower/upper confidence interval 86.6–117.4). Based on these data, the total number of AIBD patients was calculated to be 1351 in the total population of 13 325 677 children in Germany in 2015.

The highest prevalence of all AIBD was seen in pemphigus vulgaris with 30.5 patients/million children followed by linear IgA disease with 24.5/million and bullous pemphigoid with 4.9/million children. Lower prevalence were seen for mucous membrane pemphigoid (1.6/million), pemphigus foliaceus (0.6/million), and epidermolysis bullosa acquisita (1.2/million). The prevalence for all AIBD with ICD codes are shown in the Table 2.

Table 2.
Adjusted prevalence of autoimmune blistering diseases in patients below the age of 18 years in Germany in 2015
Diseases ICD‐10 Prevalence total(95%‐CI) Prevalence females (95%‐CI) Prevalence males (95%‐CI) Number of patients
Pemphigoid diseases

Bullous pemphigoid L12.0 4.9 (2.2–9.5) 4.5 (1.2–12.1) 5.2 (1.7–12.6) 10
Mucous membrane pemphigoid L12.1 1.6§ (0.33–4.9)

3.3 (0.7–10.2)

3
Chronic bullous dermatosis of childhood L12.2 24.5 (17.7–33.0) 25.9 (16.4–39.1) 23.2 (14.3 −35.7) 44
Epidermolysis bullosa acquisita L12.3 1.2 (0.1–4.5) 1.3 (0.03 −7.2) 1.2 (0.03–6.8) 2
Other pemphigoid disorders L12.8
Pemphigoid disorders, not further specified L12.9 14.9 (9.7–21.9) 14.3 (7.4–25.2) 15.4 (8.4–26.0) 25
Pemphigoid gestationis O26.4 0.6 (n. a.) 1.2 (n. a.) 1
Pemphigus diseases

Pemphigus vulgaris L10.0 30.5 (22.6–40.3) 27.3 (17.1–41.4) 33.5 (22.3–48.6) 50
Pemphigus vegetans L10.1 0.6§ (n.a.) 1.3 (n.a.) 1
Pemphigus foliaceus L10.2 0.6§ (n.a.) 1.3 (n.a.) 1
Brasilian pemphigus L10.3 1.8 (0.4–5.5) 2.6 (0.3–9.4) 1.2 (0.03–6.7) 3
Pemphigus erythematosus (Senear‐Usher) L10.4 0.6†† (n. a.) 1.3 (n. a.) 1
Other pemphigus disorders L10.8 1.8 (0.4–5.4) 2.5 (0.3–9.1) 1.2 (0.03–6.9) 3
Pemphigus diseases, not further specified L10.9 17.4 (11.7–24.9) 18.0 (10.1–30.0) 16.8 (9.3–27.9) 30
Other inflammatory dermatoses

Psoriasis L40 1231.5 (1178.6–1286.3) 1387.3 (1306.8–1471.5) 1095.5 (1016.6–1157.9) 2038
Alopecia areata L63 1046.1 (997.5–1096.5) 1165.2 (1091.9–1242.2) 934.8 (871.0–1002.1) 1743
Vitiligo L80 1008.2 (960.7–1057.5) 1041.8 (972.9–1114.4) 976.7 (911.8–1045.1) 1697
  • CI, confidence interval; n.a., not applicable.


  • Calculated for 1 715 882 insured individuals below 18 years of age adjusted to the general German population below 18 years based on the data of the Federal Statistical Office of Germany in 2015.


  • Per million persons below 18 years of age.


  • §

    Only female patients detected.


  • Also termed linear IgA disease.


  • ††

    Only male patients detected.

Sex distribution

The sex distribution was nearly equal in AIBD, except for mucous membrane pemphigoid. Interestingly, only female patients with mucous membrane pemphigoid were identified (Table 2).

Age distribution

Pemphigus vulgaris had a mean/median age of 10.9/12years, linear IgA disease of 5.5/3years and bullous pemphigoid of 5.5/3.5years. Two of the three patients with mucous membrane pemphigoid were in the first year of live, and one girl was 5years old. The two patients with epidermolysis bullosa acquisita were 8 and 15years of age. The age distributions for the most prevalent AIBD, i.e. pemphigus vulgaris, linear IgA disease and bullous pemphigoid, are detailed in Fig. 2.

image

Age and sex distribution of the three most prevalent autoimmune bullous diseases in children in Germany in 2015.

Discussion

Our study identifies pemphigus vulgaris as the most prevalent AIBD in minors in Germany. Pemphigus vulgaris had a prevalence of 30.5/million children accounting for 29% of the AIBD patients. In pemphigus vulgaris, autoantibodies are directed against desmoglein 3 and associated with erosions and blisters on surface‐close mucous membranes. Most frequently, mouth, pharynx and nasal mucosa are affected but lesions can also arise on larynx, oesophagus and genitalia. About half of the pemphigus vulgaris patients also develop antibodies against desmoglein 1 and show skin lesions, typically presenting with fragile blisters and erosions. Incidences of pemphigus vulgaris in children vary depending on the geographic region and population. In Europe and UK, the disease is relatively rare with only 3 of 410 patients being below 18 years of age18 but appear to be more frequent in India and Turkey.19, 20 In line with the present study, Ren et al .6 reported pemphigus vulgaris as the most common AIBD to be admitted to hospitals in the USA (8.0 patients/million/year between 2002 and 2012).

Traditionally, linear IgA disease, also termed chronic bullous dermatosis of childhood, has been regarded as the most frequent AIBD in childhood with an estimated incidence of 2/million/year in the UK.3-5 In contrast, incidences of linear IgA disease in adults were reported between 0.25 and 1.0/million/year.1 IgA is the dominant autoantibody isotype in this disease mostly directed against the soluble ectodomain of BP180 (type XVII collagen), also referred to as linear IgA disease antigen 1 (LAD‐1). While the immunopathological features appear to be identical between adult and childhood patients, the sudden onset and predilection sites in children differ from the disease in adults. In childhood, clustering and herpetiform arrangement of blisters is typical and mucosal involvement may be present (Fig. 3). In adults, eruption is polymorphic and atypical presentations are more common. In contrast to adults, linear IgA disease in minors may be triggered by infections and drugs and is associated with HLA‐B8, HLA‐DR3 and HLA‐DQw2.21, 22

image

Four‐year‐old boy with linear IgA disease with multiple erosions, crusts and erythema next to postinflammatory hyperpigmentation on the legs (a). Tense blisters in an annular pattern with a blister‐free centre, termed ‘crown of jewels’ sign, on the thenar of the right hand (b).

Our finding of pemphigus vulgaris being the most prevalent AIBD in children in Germany may be explained by the more benign course of linear IgA disease with rapid remission in most cases and a mean disease duration of about 15 months compared to pemphigus vulgaris with a mean disease duration in minors of 4.5 years23 and a risk for relapse like in adults.18, 20 This finding is in line with the observation in all AIBD patients in a similar approach in 2014 when the prevalence of bullous pemphigoid was not even threefold higher compared to pemphigus vulgaris although incidences differ by at least 10‐fold in Germany.9, 17 Another reason for the relatively high prevalence of pemphigus vulgaris in our study may be genetic background of the inhabitants in Germany, since about a third of minors living in Germany have a migration background (www.destatis.de; webpage of the Federal Statistical Office of Germany; assessed December 16, 2019) mainly from Turkey and other Mediterranean countries where the incidence of pemphigus is two‐ fivefold higher compared to patients with German background.2, 24

The two most common AIBD in our study, pemphigus vulgaris and linear IgA dermatosis, revealed a slightly different age distribution. While linear IgA disease had the highest prevalence at the age of 2–5 years, pemphigus vulgaris more often occurred in adolescence. These figures are also reflected in the literature. The onset of linear IgA disease was observed most commonly between 4 and 5 years of age and for pemphigus vulgaris between 12 and 17 years of age (Fig. 2).6, 18, 22

Bullous pemphigoid is the by far most common AIBD in adults but only the third prevalent in children in our study. So far <100 cases of childhood bullous pemphigoid have been reported in the literature.25 There is only one report on the incidence of BP in children which comes from Israel, estimating the incidence at a fairly high number of 23.6/Mio/year in infants below 1 year of age.26 In 80–90%, patients develop IgG antibodies against BP180, mostly against the 16th non‐collagenous domain. Like in adults, bullous pemphigoid present with intensive pruritus, tense blisters, erosions and crusts but also erythema and urticarial lesions may appear. In contrast to adults, mucous membranes are more often affected in children in the first year of life while soles, palms and face are more often involved in children older than 1 year. After the fourth year of life, no clinical differences between children and adults with bullous pemphigoid have been reported.27 Despite disease is often severe, the prognosis is more benign than in adults with remissions within weeks to few months.28

An estimation of the coding quality may be derived from pemphigoid gestationis, an AIBD occurring during pregnancies or the postpartum period.1 In our study, pemphigoid gestationis was coded only once in a 16‐year‐old girl but not in younger girls or boys. The coding quality was also probed by comparing the prevalence of other inflammatory dermatoses in our dataset, i.e. psoriasis (L40), vitiligo (L80) and alopecia areata (L63) with figures from the literatures. While for vitiligo and alopecia areata, the calculated prevalence of 0.1% was comparable with published data,29, 30 the prevalence for psoriasis (calculated to 0.12%),was slightly lower than the prevalence reported for German minors with 0.45% and Romanian school children aged between 6 and 12 years with 0.27%.31, 32 This difference may reflect a possible underestimation of the prevalence of childhood AIBD in our study.

The strength of the present study was the relatively large study group comprising nearly 13% of the German population below the age of 18 years. Healthcare insurance is mandatory in Germany, and 99.9% of inhabitants were insured in 2015. Insurance rates are fairly identical for all companies, and companies cannot refuse patients; therefore, our data relatively well reflect the entire population in Germany.

An intrinsic caveat of the study was its reliance on the coding quality of the medical personnel. While obvious miscoding was only detected in a single patient indicating a coding error rate of only 0.6%, a relatively high number of unspecific codes (L10.8, L10.9 and L12.9) that accounted for about a third of AIBD diagnoses was found. This may be due to the coding procedure not considering the sophisticated nomenclature of AIBD or not appreciating the subtle differences between the different codes and the AIBD as discussed previously.17, 33

In summary, we calculated the prevalence of AIBD in Germany to be 101.1/million (0.01%) children in 2015 resulting in a total number of 1,351 patients with AIBD below the age of 18 years. Due to the rarity of AIBD in minors, these patients should be managed in specialized centres and a multidisciplinary team including paediatric dermatologists and if unavailable, dermatologists together with paediatricians.

Acknowledgement

This work was supported by structural grants from the Deutsche Forschungsgemeinschaft through CRU 303 Pemphigoid Diseases and Excellence Cluster 2167/1 Precision Medicine in Chronic Inflammation (to D.Z. and E.S.).

    Contributions

    Franziska Hübner analysed the data and wrote the manuscript. Inke R. König and Roland Linder prepared the data and supported, like Maike M. Holtsche, the data analysis. Detlef Zillikens discussed the data and reviewed the manuscript. Enno Schmidt designed the study and wrote parts of the manuscript.

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