Autoimmune Bullous Diseases Among Children

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES FACULTY OF MEDICINE

FINAL MASTER’S THESIS

Autoimmune Bullous Diseases Among Children

Author: Benno Alexander Fiedler

Supervisor: Prof. dr. Skaidra Valiukevičienė

LSMU KK Department of Dermatology & Venereology

Kaunas, 2018 – 2020

TABLE OF CONTENTS

1. SUMMARY ... 3

2. PREAMBLE ... 4

3. INTRODUCTION ... 5

4. AIMS & OBJECTIVES ... 6

5. LITERATURE REVIEW ... 6

6. METHODS ... 8

7. RESULTS ... 10

7.1. Linear IgA Disease ... 11

7.1.1. Epidemiological data ... 11

7.1.2. Clinical presentation ... 11

7.1.3. Diagnostics ... 12

7.1.4. Treatment ... 13

7.2. Bullous Pemphigoid ... 15

7.2.1. Epidemiological data ... 15

7.2.2. Clinical presentation ... 15

7.2.3. Diagnostics ... 16

7.2.4. Treatment ... 16

7.3. Pemphigus Vulgaris and Pemphigus Foliaceus ... 17

7.3.1. Epidemiological data ... 17

7.3.2. Treatment ... 17

7.4. Dermatitis Herpetiformis Duhring ... 18

7.5. Epidermolysis Bullosa Acquisita ... 18

8. DISCUSSION ... 19

9. CONCLUSION ... 23

10. REFERENCES ... 24

11. ANNEXES ... 26

1. SUMMARY

Title: Autoimmune bullous diseases among children Author: Benno Alexander Fiedler

Aim: To conduct a systematic review of the available studies about autoimmune bullous diseases among children including data on the epidemiology, clinical presentation, diagnostic features, treatment modalities and outcomes.

Objectives: 1. To investigate the prevalence of AIBDs among children in comparison with the age and sex of the subjects

2. To determine the most common clinical and diagnostic features of AIBDs in children

3. To conduct a review of treatment regimens and outcomes of AIBDs in children Methods: The MEDLINE (PubMed) online database was searched for retrospective studies and

case series (n > 2) on autoimmune bullous diseases in children featuring data on the epidemiology, clinical presentation, diagnostic features, treatment modalities, or outcomes which were published between 2009 and 2019 by using the search term

‘autoimmune bullous diseases among children’. The PRISMA scheme was used for recording the course of the search and applying the predefined eligibility criteria.

Results: A total of 14 studies and 180 patients were included in the systematic review, respectively. The extremities were affected by bullous pemphigoid and linear IgA disease most often. The latter was characterized by the lowest age of onset and the shortest time to remission. Dapsone and systemic steroids were the most popular and drugs for treatment and showed to be effective in many cases. Sometimes other drugs had to be added in order to achieve remission.

Conclusions: Autoimmune bullous diseases among children seem to develop more frequently in males than in females, usually take a generalized course and specific lesions arise on the extremities most commonly. Dapsone and systemic steroids are the drugs of choice but the treatment may be complicated, last long and require a multidrug regimen.

Keywords autoimmune blistering disease in children; chronic bullous dermatosis of childhood;

linear IgA disease in children; bullous pemphigoid in children; pemphigus in children

2. PREAMBLE

Acknowledgement

Herewith, I would like to thank my supervisor Prof. dr. Valiukevičienė for her professional support.

Conflict of interests

The author declares no conflict of interest.

Definitions

Linear IgA disease. Autoimmune diseases which is characterized by the deposition of IgA-antibodies against BP180 at the dermoepidermal junction causing the emergence of stable blisters.

Bullous pemphigoid. Autoimmune diseases which is characterized by the deposition of IgG-antibodies against BP180 and BP230 at the dermoepidermal junction leading to the development of stable blisters.

Pemphigus vulgaris. Autoimmune diseases which is characterized by the intraepidermal deposition of IgG-antibodies against desmoglein-1 and/or desmoglein 3 and the formation of acantholytic and instable blisters which rupture easily.

Pemphigus foliaceus. Autoimmune diseases which is characterized by the intraepidermal deposition of IgG-antibodies against desmoglein-1 leading to the emergence of acantholytic instable blisters on the skin whereby mucous membranes are spared.

Abbreviations

PRISMA Preferred reporting items for systematic reviews and meta-analyses AIBD Autoimmune bullous disease

LAD Linear IgA disease IIF Indirect immunofluorescence

BP Bullous pemphigoid MTX Methotrexate

PV Pemphigus vulgaris MMF Mycophenolate mofetil

PF Pemphigus foliaceus AB Antibiotic

DHD Dermatitis herpetiformis Duhring RTX Rituximab EBA Epidermolysis bullosa acquisita

BMZ Basement membrane zone

DIF Direct immunofluoresence

3. INTRODUCTION

Autoimmune bullous diseases constitute a group of rare diseases affecting the skin that are characterized by destruction of adhesive molecules of skin cells by autoantibodies which results in longitudinal detachment of its layers and the formation of fissures. Clinically, the fissures become overt in the form of fluid-filled blisters which are prone to rupturing and leaving erosions behind. The types of autoantibodies and affected antigens, respectively, determine the disease features and clinical characteristics. The causal treatment modalities aim at counteracting the uncontrolled immuneresponse to the autoantigens by mainly using medications which suppress the immunesystem.

The size, physical properties and distribution of the blisters vary depending on the disease.

Whereas, for instance, pemphigus diseases present with quite instable blisters that are prone to spontaneous rupturing, bullous pemphigoid and linear IgA dermatosis give rise to more stable blisters which rupture upon extrinsic physical force effect. This fact stems from the microscopic location of the inflammation across the layers of the skin.

Therefore, histological examination of biopsies of skin parts affected by the blisters form an essential step for diagnosing an autoimmune bullous disease. However, in order to prove the diagnosis and to tell the different entities apart from one another, immunofluorescence microscopy has to be performed. The direct type is usually the first one to be performed and can prove the diagnosis in many cases. However, there exists an indirect type as well and its diagnostic properties are superior to the ones of the direct form but its conduction is more complex and time-consuming than that of the former one.

The treatment of these kind of diseases is complex in many cases and consists of a multidrug regimen. Suitable drugs include corticosteroids and immunosuppressants, such as azathioprine, mycophenolate mofetil, or colchicin as well as dapsone and other antibiotics which have been shown to be effective in the treatment of linear IgA disease. Adverse reactions to the mentioned drugs arise from time to time and ever and anon the treatment must be discontinued. The responses to the treatment vary, too. Sometimes only a few weeks of treatment are required to achieve complete remission. However, many cases are not easy to treat and treatments lasting for several months are needed or complete remission off therapy cannot be achieved. Disease relapses are frequent among this group of diseases.

New studies suggest that rituximab, a monoclonal anti-CD20-antibody, is effective in the treatment of refractory disease.

In general, there are only a few studies about AIBDs among children with small sample sizes

available. Linear IgA disease is reported to be the most common AIBD of childhood, followed by

bullous pemphigoid, which often affects infants. The purpose of this review is to collect the available

data and to display promising data, especially on the treatment.

4. AIMS & OBJECTIVES

5. LITERATURE REVIEW

In total, 14 studies which were published between 2009 and 2019 are included in the systematic review.

They are summarized in Table 1. 8 of which are retrospective studies and 6 are case series. 9 were published in Europe (Denmark, Turkey Italy, France, Serbia, Germany), 2 in Asia (Singapore, India), 2 in Africa (Tunisia), and 1 in South America (Argentina).

The two studies conducted by Schwieger-Briel et al. and Bilgic-Temel et al. are combined studies consisting of a case series and a literature review each. Since they presented their own cases (n > 3), these studies were included in this review.

The retrospective studies conducted by Lings K. et al. and Genovese G. et al. included adults in their study population as well. However, after these studies were assessed for eligibility, they were found to be contributing to this review since the information that concern children are well-distinguishable from that of the adults.

The ways the authors presented the information vary considerably across the studies. While some studies are focused on treatment tactics, such as Bilgic-Temel et al., there are others which focus more on clinical presentation, i.g. Monia K. et al. By far not all of the studies which feature one or more diseases of concern present all the information wanted for this review. Therefore, the results of the analyses conducted in this review are always referred to the individual size of the samples that were found to be useful to be included in the different analyses.

Aim: To conduct a systematic review of the available studies about autoimmune bullous diseases among children including data on the epidemiology, clinical presentation, diagnostic features, treatment modalities and outcomes.

Objectives: 1. To investigate the prevalence of AIBDs in comparison with the age and sex of the subjects

2. To determine the most common clinical and diagnostic features for AIBDs in children

3. To conduct a review of treatment regimens and outcomes for AIBDs in children

Table 1. Presentation of the included literature

No. Authors Year Country Title

1 Lings K. et al. 2015 Denmark Linear IgA Bullous Dermatosis: A Retrospective Study of 23 Patients in Denmark

2 Kenani N. et al. 2009 Tunisia Childhood Linear IgA Bullous Dermatosis in Tunisia 3 Monia K. et al. 2011 Tunisia Linear IgA bullous dermatosis in Tunisian children: 31 cases 4 Salman A. et al. 2017 Turkey Autoimmune bullous disease in childhood

5 Kong Y. et al. 2015 Singapore Retrospective Study on Autoimmune Blistering Disease in Paediatric Patients

6 Genovese G. et al. 2019 Italy Linear IgA bullous dermatosis in adults and children: a clinical and immunopathological study of 38 patients

7 Welfringer-

Morin A. et al. 2018 France Long-term evolving profile of childhood autoimmune blistering diseases: Retrospective study on 38 children

8 Vinay K. et al. 2014 India Successful use of rituximab in the treatment of childhood and juvenile pemphigus

9 Gajic-Veljic M. et

al. 2009 Serbia Juvenile bullous pemphigoid: the presentation and follow-up of six cases

10 Schwieger-Briel

A. et al. 2014 Germany Bullous pemphigoid in infants: characteristics, diagnosis and treatment

11 Diaz M.S. et al. 2019 Argentina Linear IgA Bullous Dermatosis: A Series of 17 Cases 12 Baroero L. et al. 2017 Italy Three case reports of post immunization and post viral Bullous

Pemphigoid: looking for the right trigger

13 Taquin H. et al. 2016 France Spectrum of Clinical Responses to Therapies in Infantile Bullous Pemphigoid

14 Bilgic-Temel A.

et al. 2019 Turkey Rituximab therapy in pediatric pemphigus patients: A retrospective analysis of five Turkish patients and review of the literature

No. Study design Period of

Investigation Inclusion Criteria

1 Retrospective Monocentric 1972 – 2014 All patients diagnosed with LABD

2 Retrospective Monocentric 1987 – 2006 All patients younger than 16 y.o. diagnosed with LABD 3 Retrospective Monocentric 1976 – 2007 Children < 16 y.o. diagnosed with LABD 4 Retrospective Monocentric 2005 – 2014 Children < 16 y.o. diagnosed with AIBD 5 Retrospective Monocentric 1998 – 2012 Children < 18 y.o. diagnosed with AIBD

6 Retrospective Monocentric 2006 – 2018 All patients diagnosed with LABD; children younger than 16 y.o.

7 Retrospective Monocentric 1993 – 2015 Children < 16 y.o. diagnosed with AIBD 8 Retrospective Monocentric 2010 – 2013 Pts. Diagnosed with PV/PF + Treatment with RTX 9 Case series Monocentric 1983 - 2007 Children < 18 y.o. diagnosed with BP and treated at the center 10 Case series Monocentric Not indicated Children were infants seen at the center

11 Retrospective Monocentric 2003 - 2017 All children treated for LABD at the center. Age limit not defined.

12 Case series Monocentric 2001 - 2016 Children diagnosed with BP seen at the center

13 Case Series Monocentric Not indicated Children were infants seen at the center

14 Case Series Multicentric Not indicated Children with PV + Treatment with RTX

6. METHODS

The MEDLINE (PubMed) online database was searched for retrospective studies and case series (n > 2) on AIBDs among children displaying the epidemiological data, clinical presentation, diagnostics, treatment modalities, or outcomes published between 2009 and 2019 using the search term ‘autoimmune bullous diseases among children’.

Inclusion criteria:

- Retrospective study or case series with a sample size not smaller than 3 - Studies were published in the past 10 years (from 2009 through 2019) - Study must have inluded 3 children at least aged < 18 years

- Study must feature at least clinical presentation or treatment - Study must display the patients individually

- Patients were followed-up for at least 1 year - Study must be written in English language

- The countries where the studies were conducted were of no importance

Exclusion criteria:

- Literature reviews, systematic reviews, case reports, cohort studies, and prospective studies - Studies that had only adults included

- Studies about solely laboratory or biochemical aspects of AIBDs

The countries where the studies were conducted were of no importance at all.

The PRISMA scheme was used to document the course of the search and reasons why some literature was excluded. Using the above-mentioned search term and after setting the relevant period of publication a total of 141 studies were identified. After screening the abstracts of those studies, 86 could be excluded straight away for the reasons named in Fig.1. 16 of the 86 articles were not written in English. The remaining 55 studies were checked for eligibility by assessing the full-text articles. Thereby, another 41 records could be excluded for the reasons mentioned in Fig.1. 7 of the 41 could not be accessed through Pubmed. In total, 14 studies were included in the systematic review: 8 retrospective studies and 6 case series.

Keywords: autoimmune blistering disease in children; chronic bullous dermatosis of childhood; linear

IgA disease in children; bullous pemphigoid in children; pemphigus vulgaris in children.

Figure 1. Documentation of the literature search according to the PRISMA criteria

7. RESULTS

In 14 studies published between 2009 and 2019, 180 children that suffered from autoimmune bullous diseases were identified in total.

Due to the fact that pemphigus foliaceus is a variant of pemphigus vulgaris that is characterised by the presence of IgG-autoantibodies against desmoglein-1 as opposed to pemphigus vulgaris having IgG- autoantibodies against both desmoglein-3 and desmoglein 1, the data concerning the two diseases were condensed. Furthermore, Welfringer-Morin A. et al. did not offer the opportunity to distinguish between the two.

Table 2. Number of children included in the studies according to disease.

No. Authors Year Country Type of Study PV/PF BP IgA DHD EBA

1 Lings K. et al. 2015 Denmark Retrospective 0 0 7 0 0

2 Kenani N. et al. 2009 Tunisia Retrospective 0 0 25 0 0

3 Monia K. et al. 2011 Tunisia Retrospective 0 0 31 0 0

4 Salman A. et al. 2017 Turkey Retrospective 2 2 5 0 0

5 Kong Y. et al. 2015 Singapore Retrospective 2 2 5 0 0

6 Genovese G. et

al. 2019 Italy Retrospective 0 0 11 0 0

7 Welfringer-

Morin A. et al. 2018 France Retrospective 10 4 18 5 1

8 Vinay K. et al. 2014 India Retrospective 10 0 0 0 0

9 Gajic-Veljic M.

et al. 2009 Serbia Case series 0 6 0 0 0

10 Schwieger-Briel

A. et al. 2014 Germany Case series 0 5 0 0 0

11 Diaz M.S. et al. 2019 Argentina Case series 0 0 17 0 0

12 Baroero L. et

al. 2017 Italy Case series 0 3 0 0 0

13 Taquin H. et al. 2016 France Case Series 0 4 0 0 0

14 Bilgic-Temel A.

et al 2019 Turkey Case Series 5 0 0 0 0

SUM 29 26 119 5 1

7.1. Linear IgA Disease

In total, 119 cases of LAD were identified in 8 studies: 2 of them were conducted in Tunisia (56 cases) (1) (1,2) and one each in Denmark (7 cases) (3), Turkey (5 cases) (4), Singapore (5 cases) (5), Italy (11 cases) (6), France (18 cases) (7), and Argentina (17 cases) (8), respectively.

7.1.1. Epidemiological Data

Among the 119 patients, 76 were male and 43 patients were female yielding an overall male-to-female ratio of 1.74:1 (range: 1.33 – 2.67). The mean age of onset was 5.6 years of age (range: 0.5 – 16 years).

The highest age of onset is not considered to be expressive since it is preset by the inclusion criteria of the studies themselves. Kenani et al. presented an estimated incidence rate of 1.25 cases per 1 million population per year.

7.1.2. Clinical Presentation

Type of eruption. The data of 41 children presented in Monia K. et al. and Genovese G. et al. could be screened for this characteristic. They described the lesions as vesicular, vesicobullous or bullous depending on the size of the eruption. Monia K. et al. reported that vesicobullous lesions occurred most often, whereas Genovese G. et al. claimed that bullous lesions arose most frequently. An erythematous base on which the blisters presented as well as erosions were obvious in almost 50 % of cases. The so- called ‘String-of-Pearls’ sign which is a typical presentation of the organization of the blisters in linear IgA disease was described in 56 % of reported cases. Giovanni G. et al. claimed that it occurred significantly more often in children than in adults along with perioral skin and mucous membrane involvement. Prodromal pruritus was described by Monia K. et al. in approximately 50 % of cases. The other studies did not mention any subjective symptoms at all.

Distribution of the lesions. 86.5 % of the patients presented with a solely cutaneous disease whereas

involvement of the mucous membranes was rare and reported only in 13.5 % of them. In all cases,

multiple regions of the body were affected by the blisters. 77.1 % out of 88 patients had involvement of

the lower limbs, which is the part of the body which was involved by far most frequently, followed by

the face (58.3 %), and the upper limbs (55.2 %). Ears, buttocks and genitalia were rarely affected.

Figure 2. Distribution of the lesions among children affected by LAD [%]

7.1.3. Diagnostics

Differential diagnoses. Monia K. et al. reported that it was difficult in several cases to find the formulate diagnosis in the first place since the physical examination of the patients suggested an infectious bullous dermatosis. Lings K. et al. explained that the lesions could resemble bullous impetigo or bullous erythema multiforme as well as blisters typical of varicella or herpes virus infections.

Drug-induced LAD. Drug-induced forms of LAD were described scarcely. For instance. Kenani L. et al. presented a case in which a patient developed the disease several days after the administration of vancomycin. Diaz M. et al. reported about two LAD patients who were vaccinated against the flu and varicella 2 weeks before the onset of disease.

Histology. Histological examination was done for 82 patients. In 61.1 % of cases, subepidermal bullae were identified along with dermal neutrophilic infiltrate. 14.4 % of cases had eosinophilic infiltration instead of neutrophilic. Lastly, combined neutrophilic and eosinophilic infiltrate was found in 16.7 % of cases. However, in 7.8 % no cellular infiltrate was found. Genovese G. et al. presented 3 children whose skin biopsy specimens showed neutrophilic microabscesses at the tip of dermal papillas.

Direct immunofluorescence. DIF was performed for 114 patients. Specimens 72.1 % of which showed linear depositions of IgA only at the basement membrane zone. In specimens of 25 patients, the IgA depositions were associated with either IgG (7.4 %), IgM (4.9 %), C3 complement (6.6 %) or C1q

58,3

24,0

6,3 10,4

46,9

55,2

77,1

30,2

8,3 9,4 13,5

0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 90,0

Face Scalp Ears Neck Trunk Upper

Limbs Lower

Limbs Perineum Buttocks Genitalia Mucosa

complement (1.6 %). The remaining 12 specimens showed triple depositions of IgA and two of the aforementioned associated substances.

Indirect immunofluorescence. IIF was by far less frequently conducted. In total, only 38 specimens were tested. 29 (76.3 %) of which were tested positive. Out of the 29 positives, 22 (75.9 %) were positive for IgA, the rest were positive for IgG. 17 specimens (44 %) were tested negative.

Correlation with the HLA-antigen. Lings K. et al., Monia K. et al., and Kenani N. et al tested several of their patients for the HLA-B8 and HLA-D3 haplotypes and most of them were positive.

7.1.4. Treatment

Drugs used for treatment. The data of 107 patients could be evaluated regarding this characteristic.

Dapsone was by far the most commonly used drug. 84.1 % received this drug during their therapy either as monotherapy of in combination with other drugs. 39.3 % were administered a systemic corticosteroid and 14 % received a topical corticosteroid. A little number of patients were treated with sulfonamides such as sulphapyridine or sulphasalazine, beta-lactam antibiotics, namely amoxicillin and oxacillin. A few patients received erythromycin. Immunosuppressive agents apart from corticosteroids, namely, azathioprine or methotrexate were used in one patient each.

Drug regimens used for treatment. The regimens used for treating LAD differed largely with regards to the drug combinations. For 41 out of 102 patients (40.2 %), dapsone monotherapy was enough in order to achieve remission. The dose of dapsone varied between 0.5 and 2 mg/kg/d in most cases, however Diaz M. et al. dosed dapsone to up to 3 mg/kg/d. Fixed dosages ranging between 25 and 100 mg/d were used as well (1). 26 patients (25.5 %) were given a combination of dapsone and a systemic corticosteroid such as prednisone or prednisolone, 5 (4.9 %) patients received systemic corticosteroids as monotherapy and in 9 cases (8.8 %) dapsone was combined with a topical steroid. Systemic corticosteroids were admininistered at 0.5 to 1 mg/kg/d in most cases, however, doses to up to 2 mg/kg/day were described. Only a few patients were treated with combinations or monotherapies of others of the aforementioned drugs and, thus, were not popular with regards to the treatment. For instance, Kenani N. et al. successfully used oral oxacillin at 50 mg/kg/d and erythromycin at 50 mg/kg/d in one case each. The mean duration of treatment was 23.6 months (range: 1 – 129 months). The patients of Kenani N. et al. were treated the shortest (3 – 60 months) whereas Welfringer-Morin A. et al.

presented the most. In several studies rituximab was prescribed either in a body-weight-dependent

dosing scheme (375 mg/m

twice) or a fixed-dose scheme (500 mg twice per day) (5,9,10). All of the children achieved remission.

Figure 3. Drug regimens used for treatment among children affected by LAD

Adverse drug reactions. Overall, side effects of the drug treatment occured rarely. Monia K. et al., Kenani N. et al. presented 7 individuals which developed methemoglobinemia and anemia as a result of treatment with dapsone. However, they were successfully treated by reducing the dose of the drug. Vinay K. et al. mentioned that four of their patients developed adverse drug reactions to the administration of rituximab – ranging from mild forms like uneasiness and chills to even angioedema – and reduction of the dose and supportive admininistration of systemic steroids and antihistamines cured them. One patient in Kong Y. et al. suffered from neutropenic sepsis as a complication of the treatment with rituximab.

Outcome. All in all, the vast majority of the patients achieved complete remission. Only a few of them were in remission on therapy at the time when the studies were publicized. But in many cases the first- line treatment did not lead to full remission and adjustments in the drug regimen had to be made.

Relapses were relatively common in general; however, the number of relapses was not distributed evenly across the studies: Genovese G. et al. had one patient only experiencing relapse of the disease whereas Welfringer-Moring A. et al. reported about 13 out of 18 patients suffering from relapse. As Diaz M. et al. suggested, relapse can occur following an infection of the upper respiratory tract. Several patients were lost to follow-up and, thus, their treatment outcome could not be evaluated.

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7.2. Bullous Pemphigoid

A total of 26 children having suffered from bullous pemphigoid were collected through the search: 2 patients from Turkey (4), 2 from Singapore (5), 8 from France (7,11), 6 from Serbia (12), 5 from Germany (13) and 3 from Italy (14).

7.2.1. Epidemiological Data

15 patients were male and 11 were female giving an overall male-to-female ratio of 1.36:1. The youngest child who suffered from BP was 9 days old only (11). The vast majority of patients included in this study were younger than 2 years of age, while Gajic-Veljic et al. and Kong et al. reported about patients that were considerably older – up to 17 years of age.

7.2.2. Clinical Presentation

The lesions were described to range in size from small vesicles to large bullae. They were distributed in various locations across the surface of the skin; however, upper and lower limbs were affected most frequently. Involvement of the perineum and buttocks were not described at all. Mucosal surfaces were affected in 3 cases. Schwieger-Briel et al., Baroero et al., and Taquin et al. were the only authors that decribed the lesions to affect the hands and feet and 100 % of their patients presented with that; most of them even having lesions on the palmar and plantar surfaces.

Figure 4. Distribution of lesions among patients suffering from BP.

63,6

18,2 18,2

36,4

81,8

90,9

81,8

0,0 0,0

27,3 27,3

0,0 10,0 20,0 30,0 40,0 50,0 60,0 70,0 80,0 90,0 100,0

Face Scalp Ears Neck Trunk Upper

Limbs Lower

Limbs Perineum Buttocks Genitalia Mucosa

7.2.3. Diagnostics

Histology. Specimens of 12 patients (5,11,12) were investigated histologically. 7 of which showed subepidermal bullae with eosinophilic infiltrate. The remaining 5 were described in Gajic-Veljic et al.

and revealed subepidermal bullae with combined infiltrates consisting of eosinophils, neutrophils, fibrin, and/or mononuclear cells along with hydropic keratinocytic generation.

Direct immunofluorescence. 19 specimes were investigated by DIF (5,11–14) and 12 of which showed depositions of both IgG and complement C3 along the BMZ. 4 had IgG depositions only. The remaining 3 had depositions of at least 3 components including IgG, C3-complement, and IgA or IgM.

Indirect Immunofluorescence. IIF was performed in 17 cases (5,11–13), 14 of which were positive for IgG. Kong et al. and Schwieger-Briel et al. described the depositions of IgG as ‘roof-patterns’ in 100 % of the positively tested specimens.

Other findings. Immunoblotting was performed in 11 cases (5,11–14) in which the presence of autoantibodies against BP180 was confirmed in 100 %. Autoantibodies against BP230 were detected in one case only (5). Schwieger-Briel et al., Baroero L. et al., and Taquin H. et al. presented patients that were found to have eosinophilia ranging from mild (5 %) to severe (52 %). These authors also linked several cases of BP to the diphtheria-pertussis-tetanus vaccine as well as to vaccines covering poliomyelitis, Haemophilus influenzae b, hepatitis B and rotavirus. The disease-specific lesions occurred a few days to 4 weeks after the administration of the vaccine. Baroero L. et al. even reported about a case which was linked to HSV-1 infection.

7.2.4. Treatment

The treatment methods of 17 patients could be evaluated. In 8 cases, systemic corticosteroids were used in monotherapy where the dose ranged between 0.5 and 1 mg/kg/d (12). In 5 cases a systemic steroid was combined with either a topical steroid or dapsone (7,12). For instance, Gajic-Veljic M. et al.

added dapsone to a preexisting treatment with oral prednisone about 1 to 2 weeks after the beginning of

the treatment at 1.3 to 1.7 mg/kg/d in three cases if the patients presented with severe disease. In 4 cases,

topical steroids were the only drugs used (7,11). Salman A. et al. treated both of their patients with

intravenous immunoglobulins and once methotrexate was used for treatment-resisting disease. The time

to remission ranged from 48 hours to 37,5 months (mean: 14.3 months). Relapses were rare – only 2 of

18 had relapses during the follow-up.

Figure 5. Drug regimens used for treatment of BP.

7.3. Pemphigus Vulgaris and Pemphigus Foliaceus

30 cases of PV/PF could be identified in a total of 5 studies: 2 from Turkey (4), 1 from India (10), 1 from France (7), and 1 from Singapore (5). The information that is concerned with the clinical presentation and diagnostics of PV and PF found were not sufficient to contribute to this thesis.

7.3.1. Epidemiological Data

20 males and 9 females were found to suffer from PV or PF resulting in a male-to-female ratio of 2.2:1.

The youngest patient affected was 2 years of age while the oldest was 17 which is limited by the upper age-related inclusion criterion. The mean age of onset is 10.7 years (range: 6.5 – 12.4 years).

7.3.2. Treatment

Drugs used for treatment. Systemic use of corticosteroids and dapsone was frequent and these two drugs seem to be the first drugs to choose. Other drugs, such as antibiotics, colchicine, azathioprine, methotrexate, MMF, and IVIg were used more rarely. A promising drug to treat PV/PF in case of resistant disease or failure of preceding treatment is rituximab as an additional drug, which was described by Bilgic-Temel et al. and Vinay et al. in more detail.

17,6

11,8

47,1

23,5

0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0

Dapsone + Systemic Steroid Topical + Systemic Steroid Systemic Steroid Mono Topical Steroid Mono

Rituximab. The aforementioned two authors (10,15) used rituximab for treating severe, complicated PV/PF in two different regimens: a fixed-dose regimen consisting of two 500 mg RTX administrations 15 days apart and a variable regimen of 375 mg/m

RTX administered 15 days apart, which is dependent on the bodys surface area. Either of the two regimens are reported to be equally effective. 66% of the patients were in complete remission at the time when the studies were published.

7.4. Dermatitis Herpetiformis Duhring

The only study that covers this disease was done by Welfringer-Morin et al. in France. 5 Patients (2 males and 3 females) were evaluated. There is no information given about diagnostics or clinical presentation. 4 patients were treated with a triple therapy consisting of gluten-free-diet, topical corticosteroid, and dapsone. The 5

patient did not get the dapsone. The mean duration till treatment response lasted 0.7 months (range: 0.25 – 2 months) and the total duration of treatment lasted 40 months (range: 9 – 108 months). All patients experienced at least one relapse: 3 off-treatment and 2 on-treatment with the relapses occuring after 4.35 months on average (range: 0.5 – 14). Complete remission was achieved after a mean period of 37.2 months (15 – 86 months).

7.5. Epidermolysis Bullosa Acquisita

Since only 1 patient was described in Welfringer-Morin et al. and the minimal number of required

patients for this review was not met, further evaluation of this disease was not brought forward.

8. DISCUSSION

The clinical data on autoimmune bullous diseases among children are scarce and to be interpreted carefully. The fact that many of the included studies present their results in different ways with one presenting a certain characteristic in a way that makes it hardly comparable with that of another makes it difficult to categorize and summarize the given data in the desired way. Basic information, such as the epidemiological data, were described in a uniform way as opposed to the treatment regimes, which were hard or not at all to comprehend, especially, when a lot of drugs were used with one being stopped at a certain point during the treatment process and another being introduced thereafter. The only disease being described by numerous references is the linear IgA disease whose case numbers made up about 66% of all the cases of AIBDs taken into account in this review. As opposed to this, pemphigus and bullous pemphigoid made up 16% and 14% of all the cases considered in this review, respectively. In addition, the majority of literature does not thoroughly focus on the clinical presentation of these diseases and, therefore, the amount of information considered in this paper is not very expressive.

In general, AIBDs seem to affect male individuals more frequently than females. Except for Gajic-Veljic M. et al. who found a female predominance of BP all the other studies evaluated in this review proved otherwise. However, Waisbourd-Zinman O. et al. conducted a retrospective study on infantile BP and they state that BP has a female predominance (16). Since they included a considerably higher number of patients in their study, their results are of greater scientific importance. On the other hand, Schwieger- Briel A. et al. contradicts that because they could not confirm a statistically significant female predominance (13). Pemphigus seems to have the highest male predominance as compared with LAD and BP in this study. On the other hand, bullous pemphigoid seems to have the lowest male predominance. As for the age of onset, the considerable number of infantile BP cases suggests that this disease affects the youngest children more often as compared with the other diseases. However, juvenile cases of BP were mentioned as well. Opposed to that, pemphigus was found to develop in the older children population more frequently with a mean age of onset of 10.7 years.

The mean age of onset of LAD was found to be 5.6 years in this review. For instance, Sansariqet al.

claimed that the disease affects children usually younger than 5 years of age (17). Thus, the patients evaluated here were a bit older than the literature suggests.

As some literature (1,17) claims that the most common sites of affection of LAD-specific lesions are the

abdomen and perineum, the children in this review were found to present with lesions on the face and

Dyspigmentations of the affected skin frequently occurs after the lesions resolved (17), however, none of the authors mentioned anything like that.

Patients suffering from LAD seem to have a predisposition to developing this disease if they have the HLA-B8 or DR3 haplotypes. In this review, individuals presented by Lings K. et al., Monia K. et al., and Kenani N. who tested their patients for this genetic variant were tested positive. Evidence in the literature was established that there is indeed a correlation between the occurrence of the disease and the presence of HLA-B8 or DR3 haplotypes (18). Furthermore, the presence of HLA-B8 haplotype was found to be a positive predictive factor for the outcome of the disease and may be associated with a mild course of the disease (19).

The golden standard for diagnosing LAD is DIF. Typical findings suggestive of LAD are linear depositions of IgA along the basement membrane zone either associated with other deposits, such as IgG, IgM, or components of the complement system or on its own. However, in most cases IgA is not associated with any of the aforementioned substances. Interestingly, Horiguchi Y. et al. and Mulyowa et al. found out that with increasing age the likelihood of IgA being associated with IgG increases with age (19,21). IIF is another diagnostic method, which is said to have lower sensitivity as compared with DIF and is not part of the usual diagnositv algorithm of LAD. Nevertheless, in this review 76 % of cases had a positive IIF result. Interestingly, the literature suggests that positive IIF-testing is more frequent among children than among adults (22). Histological examinations of perilesional specimens showed characteristic features of LAD, namely subepidermal bullae which are infiltrated with neutrophils. But interestingly, eosinophilic infiltrates were reported as well.

Up to this day, there were no randomized, placebo-controlled, double-blind studies conducted on the

treatment of LAD. Therapeutical recommendations rely on experiences of case series and reports as well

as the treatment of the adult form of LAD. Dapsone is the drug of choice in this regard and can be

administered at 0.5 to 3 mg/kg/d. The appropriate dose should be chosen according to the severity of

disease. Since methemoglobinemia is a not-so-rare reaction to the treatment with dapsone glucose-6-

phosphate-dehydrogenase levels should be determined before and during the treatment. However, only

a few authors reported about adverse drug reactions to dapsone and even in the case of

methemoglobinemia, tapering the dose of dapsone was enough to lower its concentration. If the disease

is severe or the treatment with dapsone is not sufficient to achieve remission, a systemic steroid, such as

prednisone or prednisolone, can be administered concomitantly at 0.5 to 1 mg/kg/d. Treatments with

other drugs, in particular other antibiotics, were successful in a few cases, however, the experience with

using these drugs is lower as with the other two aforementioned ones and should be used carefully. The

outcome of the disease is good, in general. The duration of treatment may be quite long and take many months in order to achieve complete remission off therapy, if at all. According to Sansaricq. Et al., spontaneous remissions within 5 years after the onset of the disease can be expected (17). In this study, the average time to remission is 24.6 months.

Bullous pemphigoid occurs less commonly than LAD. Usually, the disease develops under 8 years of age and a quarter of all affected children are infants (23,24). Most of the studies which are included in this review reported about children whose onset of disease was before the age of 2. However, Gajic- Veljic M. et al. and Kong Y. et al. presented individuals whose disease broke out at the age of 17, and thus, being at the border between juvenile or adolescent BP and adult BP. This disease usually manifests as generalized disease with predominant involvement of the upper and lower limbs as well as the trunk.

Palmar and plantar involvement are a typical features of this disease in the infantile subset, whereas it is not common for older children (13,17). As opposed to LAD, facial involvement is common but not as common as in LAD. Perineal and gluteal affection was not seen at all in the review studies and this seems to be in line with the current literature (17). Cases in which an outbreak of BP followed a vaccination were reported (13,14,20). However, due to the vast amount of vaccinations in young children a causality between vaccination and outbreak of BP is not justifiable (14,16).

DIF is the diagnostic tool of choice when it comes to diagnosing BP. In the majority of cases, depositions of IgG were accompanied by complement C3 (63.2 %). Simple depositions of IgG alone were observed in 21.1 % of cases only. This finding is in contrast to LAD which mostly presents with solely IgA deposits. This fact is interesting, since these two disease entities are quite similar since they share the same target antigen (BP180) although LAD is characterized by IgA deposits and BP by IgG deposits. In fact, there is evidence which suggests that LAD and BP are so similar, that they cannot be clearly marked-off of one another and the transition between the two is fluent (17). IIF can be performed as well and the results characteristic of BP usually show a so-called roof pattern of IgG antibody depositions along the basement membrane zone. In this study, roughly 82 % of the performed IIF testings were positive which is slightly higher than that of LAD. Immunoblotting is another test which is somewhat commonly used in the diagnosis of BP since it proves the target antigen attacked by the antibodies.

With regards to the treatment of BP, systemic steroids and dapsone were the drugs used most often.

However, in contrast to the treatment of LAD, a systemic steroid is used predominantly as first-line

treatment. Prednisone or prednisolone were used at 0.5 to 1 mg/kg/d. Adverse reactions were rare and

could be brought under control by tapering the dose although the literature states that roughly 40 % of

BP patients treated with systemic steroids develop severe complications even resulting in death (25). In

order to prevent that, Baroero L. et al. tried to lower the risk of that by administering antibiotics concomitantly. Roughly half of the patients included in this review were treated with a systemic steroid in monotherapy. It is commonly said that systemic steroids are the drugs of first choice for treating BP (26). Furthermore, topical steroids were used alone or in combination with their systemic counterparts at a much lesser frequency. Dapsone can be combined with a systemic steroid, if needed. The treatment outcome is good and relapses did not occur at al as apposed to LAD. And even the mean time to remission was considerably shorter than that of LAD - 14.3 months.

Based on the data of this review, pemphigus vulgaris and pemphigus foliaceus appear to have the highest male-to-female ratio – 2.2:1, which is considerably higher than that of LAD and BP. The mean age of onset was found to be 10.7 years. The youngest patient included in this review was a two-year-old.

Unfortunately, there was no data on clinical presentation and diagnostics evaluable since the authors of the studies included in this review did not specify them. Dapsone and systemic steroids were used at a similar frequency for treating pemphigus. Other immunosuppressive drugs, such as azathioprine and mycophenolate mofetil were used in 4 and 3 cases, respectively, to control the disease and even intravenous immunoglobulins were administered in 2 cases. Thereby, possible severe side effects caused by high-dose systemic steroid therapy were avoided. Topical steroids were usually used in addition to systemic drug treatment. Relapses were reported by Welfringer-Morin A. et al. and all of their patients experienced relapses throughout the course of their treatment. The overall mean time to remission was 41.6 months and, thus, is found to be the longest among the investigated diseases. Meanwhile, rituximab is commonly used as first- or second-line therapy (23). Vinay K. et al. and Bilgic-Temel A. et al.

dedicated their studies to describing the effectivity and safety of rituximab therapy. The administration of rituximab in a fixed-dose regime (500 mg twice) is to be preferred since the body-surface-dependent regime may be susceptible to dosing errors (27). The mean time to remission was 41.6 months and, thus, is found to be the longest among the investigated diseases.

The limitations of this review must be considered when reading it. The number of cases included in this

review are low, with the exception of patients affected by LAD. The low case counts underline that these

diseases are indeed very rare and since there are no large and scientifically reliable studies on this topic

available concrete treatment recommendations cannot be established and advices for treatment must be

based on case series and retrospective studies. The usage of a very high number of various drugs may

underline either the insecurity about appropriate treatment tactics of these diseases or the scientific

curiosity about finding new treatment regimens.

9. CONCLUSION

Linear IgA disease is the most well-reported autoimmune blistering dermatosis among children.

The mean age of onset is about 5.6 years but it may affect children of less than one year of age as well.

Specific lesions are most commonly of vesicular or vesiculobullous type and the extremities as well as the face are the body parts which are most frequently affected. In histological examinations, LAD presents with subepidermal blisters infiltrated by neutrophils but eosinophils can be found as well. Direct immunofluorescence microscopy confirms the diagnosis based on the presence of IgA-antibodies which may be associated with other deposits, such as IgG and IgG and components of the complement system.

Dapsone and systemic steroids are effective drugs in the treatment of LAD. The former should be administered at 0.5 to 2 mg/kg/d, however, 3mg/kg/d may be used as well. High-dose administrations should be used carefully, being aware of adverse drug reactions, such as methemoglobinemia and anemia. Systemic steroids, such as prednisolon, can be used at 0.5 – 1 mg/kg/d in monotherapy or in addition to dapsone if the severity of the disease requires it. Higher doses of up to 2 mg/kg/d may be used reluctantly. The treatment can last approximately 2 years and the outcome is overall good; however, relapses are not uncommon and may prolong the time of the treatment to full remission.

Bullous pemphigoid can affect children of any age, but infantile cases are common among the pediatric population. Specific lesions most offen arise on the trunk and extremities with the palmar and plantar surfaces being involved in particular. Facial involvement occurs somewhat less frequently in comparison with linear IgA disease but is common as well. Being aware of the low case counts, this disease commonly presents with subepidermal bullae and eosinophilic infiltrate which may be accompanied by neutrophils and fibrin. But as opposed to linear IgA disease, eosinophilic infiltrate is found more frequently. In DIF, IgG-antibodies are usually associated with C3-complement. As for the treatment options, a systemic steroid at 0.5 – 1 mg/kg/d is the drug of choice which may be coadministered with dapsone or a topical steroid if the disease is resistant to a monotherapy with steroids.

But as opposed to linear IgA disease, a systemic steroid is to be preferred over dapsone as first-line treatment. The mean time to remission on treatment is about 1 year, which is considerably shorter as in LAD. Furthermore, relapses occur by far less commonly as in LAD.

Pemphigus vulgaris and folicaceus were the least frequently reported and, thus, the conlusions to be drawn from the investigation must be considered with caution. PV/PF seem to have the highest male-to-female ratio (2.2:1) among the diseases investigated. Systemic steroids and dapsone are good drugs to treated the disease, however, recent studies suggest the usage of rituximab at 500 mg twice 15 days apart in resistant disease (10,16,26).

Generally speaking, since here are only a few studies on AIBDs available and further

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11. ANNEXES

Annex 1 Epidemiological data on children affected by LAD 27

Annex 2 Types of eruption among children affected by LAD 28

Annex 3 Distribution of lesions among children affected by LAD 29 Annex 4 Results of histological examinations of specimens from children affected by LAD 30 Annex 5 Results of DIF of specimens from children affected by LAD 31 Annex 6 Results of IIF of specimens from children affected by LAD 32 Annex 7.1 Drugs used for treatment among children affected by LAD (Part 1/2) 33 Annex 7.2 Drugs used for treatment among children affected by LAD (Part 2/2) 34 Annex 8.1 Drug regimens used for treatment among children affected by LAD (Part 1/2) 35 Annex 8.2 Drug regimens used for treatment among children affected by LAD (Part 2/2) 36 Annex 9 Shortest, longest, and mean duration of treatment among children affected by LAD 37 Annex 10 Shortest, longest, and mean time to remission among children affected by LAD 38

Annex 11 Epidemiological Data on children affected by BP 39

Annex 12 Distribution of lesions among children affected by BP 40

Annex 13 Results of histological examinations of specimens from children affected by BP 41

Annex 14 Results of DIF of specimens taken from children affected by BP 42

Annex 15 Results of IIF of specimens from children affected by BP 43

Annex 16 Results of immunoblotting of specimens from children affected by BP 44

Annex 17 Drugs used for treatment among children affected by BP 45

Annex 18 Drug regimens used for treatment among children affected by BP 46

Annex 19 Shortest, longest, and mean time to remission among children affected by BP 47

Annex 20 Shortest, longest, and mean duration of treatment among children affected by BP 48

Annex 21 Epidemiological Data on children affected by PV/PF 49

Annex 22 Drugs used for treatment among children affected by PV/PF 50

Annex 1. Epidemiological data on children affected by LAD

Name N Males Females M:F Ratio Lowest Age of

Onset [years] Highest Age of

Onset [years] Mean Age of Onset [years]

Estimated Incidence [per

million/year]

Lings K. et al. 7 4 3 1.33 0.9 4 2.7 Not evaluable

Kenani N. et al. 25 16 9 1.78 0.5 15 7.5 1.25

Monia K. et al. 31 22 9 2.44 0.7 16 5.5 Not evaluable

Salman A. et al. 5 3 2 1.5 4 14 7.4 Not evaluable

Kong Y. et al. 5 3 2 1.5 2 16 7.6 Not evaluable

Genovese G. et

al. 11 8 3 2.67 0.9 16 5.4 Not evaluable

Welfringer-

Morin A. et al. 18 10 8 1.25 0.9 13.5 5.3 Not evaluable

Diaz M.S. et al. 17 10 7 1.43 0.6 7 3.1 Not evaluable

Sum 119 76.0 43.0 --- --- --- --- ---

Average --- --- --- --- --- 5.6 ---

Annex 2. Types of eruption among children affected by LAD

Name N Vesicular Bullous Vesicobullous Erythema Erosions String-of-Pearls Sign

Lings K. et al. 0 Not indicated in study

Kenani N. et al. 25 Not indicated in study 20

Monia K. et al. 30 7 9 14 15 15 12

Salman A. et al. 0 Not indicated in study

Kong Y. et al. 0 Not indicated in study

Genovese G. et

al. 11 4 6 3 4 3 5

Welfringer-

Morin A. et al. 0 Not indicated in study

Diaz M.S. et al. 0 Not indicated in study

Sum 66 11 15 17 19 18 37

Percentage [%] --- --- --- --- --- 56

Annex 3. Distribution of lesions among children affected by LAD

Name N Face Scalp Ears Neck Trunk Upper

Limbs Lower

Limbs Perineum Buttocks Genitalia Mucosa

Lings K. et al. 0 Not indicated in study

Kenani N. et al. 25 10 10 0 0 7 0 15 15 0 0 2

Monia K. et al. 30 16 6 0 4 12 23 29 2 5 5 4

Salman A. et al. 0 Not indicated in study

Kong Y. et al. 5 0 1 1 1 4 4 5 0 0 0 0

Genovese G. et

al. 11 7 0 3 0 6 7 7 0 2 3 5

Welfringer-

Morin A. et al. 0 Not indicated in study

Diaz M.S. et al. 17 16 3 1 2 9 14 13 7 1 1 2

Sum 88 56 23 6 10 45 53 74 29 8 9 13

Percentage [%] 58.3 24.0 6.3 10.4 46.9 55.2 77.1 30.2 8.3 9.4 13.5

Annex 4. Results of histological examinations of specimens from children affected by LAD

Name N Subepidermal bulla + Dermal

neutrophilic infiltrate Subepidermal bulla + Dermal

eosinophilic infiltrate Subepidermal bulla + Combined

infiltrate No cellular infiltrate

Lings K. et al. 0 Not indicated in study

Kenani N. et al. 25 21 0 4 0

Monia K. et al. 23 1 12 4 6

Salman A. et al. 0 Not indicated in study

Kong Y. et al. 5 1 1 2 1

Genovese G. et

al. 11 6 0 5 0

Welfringer-

Morin A. et al. 18 18 0 0 0

Diaz M.S. et al. 0 Not indicated in study

Sum 88 55 13 15 7

Percentage [%] 61.1 14.4 16.7 7.8

Annex 5. Results of DIF of specimens from children affected by LAD

Name N IgA only IgA + IgG IgA + C3 IgA + IgM IgA + C1q IgA + IgG +

C3 IgA + C3 +

C1q IgA + IgM +

C3 IgA + IgM + C1q

Lings K. et al. 7 6 1 0 0 0 0 0 0 0

Kenani N. et al. 25 16 5 3 1 0 0 0 0 0

Monia K. et al. 31 12 3 5 4 2 2 2 0 1

Salman A. et al. 0 Not indicated in study

Kong Y. et al. 5 5 0 0 0 0 0 0 0 0

Genovese G. et

al. 11 6 0 0 1 0 2 0 2 0

Welfringer-

Morin A. et al. 18 18 0 0 0 0 0 0 0 0

Diaz M.S. et al. 17 17 0 0 0 0 0 0 0 0

Sum 114 80 9 8 6 2 4 2 2 1

Percentage [%] 65.6 7.4 6.6 4.9 1.6 3.3 1.6 1.6 0.8

Annex 6. Results of IIF of specimens from children affected by LAD

Name N Positive Positive IgA Positive IgG Negative

Lings K. et al. 3 2 Not indicated in study 1

Kenani N. et al. 20 12 9 3 8

Monia K. et al. 6 2 0 2 4

Salman A. et al. 0 Not indicated in study

Kong Y. et al. 2 2 2 0 0

Genovese G. et

al. 7 6 6 0 1

Welfringer-

Morin A. et al. 0 Not indicated in study

Diaz M.S. et al. 0 Not indicated in study

Sum 38 24 --- --- 14

Percentage [%] 63.1 --- --- 36.9

Annex 7.1. Drugs used for treatment among children affected by LAD (Part 1/2)

Name N Dapsone Systemic

Steroid Antihistamines Sulphapyridine Azathioprine Erythromycin Amoxicillin Oxacillin

Lings K. et al. 7 7 4 0 6 0 0 0 0

Kenani N. et al. 25 19 8 0 0 0 2 0 3

Monia K. et al. 21 19 7 0 0 0 4 1 0

Salman A. et al. 5 5 4 0 0 0 1 0 0

Kong Y. et al. 4 2 3 0 0 1 0 0 0

Genovese G. et

al. 11 10 6 0 0 0 0 0 0

Welfringer-

Morin A. et al. 17 12 0 0 0 0 0 0 0

Diaz M.S. et al. 17 16 10 1 0 0 0 0 0

Sum 107 90 42 1 6 1 7 1 3

Percentage [%] 84.1 39.3 0.9 5.6 0.9 6.5 0.9 2.8

Annex 7.2. Drugs used for treatment among children affected by LAD (Part 2/2)

Name N Salazopyrine Antibiotic Sulfasalazine Sulfamide Colchicine MTX Topical Steroid

Lings K. et al. 7 0 0 0 0 0 0 1

Kenani N. et al. 25 0 0 0 0 0 0 0

Monia K. et al. 21 0 0 0 1 0 0 0

Salman A. et al. 5 0 0 1 0 1 1 0

Kong Y. et al. 4 0 0 0 0 1 0 0

Genovese G. et

al. 11 0 0 0 0 0 0 0

Welfringer-

Morin A. et al. 17 1 1 0 0 0 0 13

Diaz M.S. et al. 17 0 0 0 0 0 0 1

Sum 107 1 1 1 1 2 1 15

Percentage [%] 0.9 0.9 0.9 0.9 1.9 0.9 14.0