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U N I V E R S I TAT I S O U L U E N S I S
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D 1410
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Anna-K
aisa Försti
OULU 2017
D 1410
Anna-Kaisa Försti
INCIDENCE, MORTALITY, COMORBIDITIES, AND TREATMENT OF BULLOUS PEMPHIGOID IN FINLAND
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;OULU UNIVERSITY HOSPITAL;MEDICAL RESEARCH CENTER OULU
A C T A U N I V E R S I T A T I S O U L U E N S I SD M e d i c a 1 4 1 0
ANNA-KAISA FÖRSTI
INCIDENCE, MORTALITY, COMORBIDITIES, AND TREATMENT OF BULLOUS PEMPHIGOIDIN FINLAND
Academic dissertation to be presented with the assentof the Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defencein Auditorium 8 of Oulu University Hospital (Kajaanintie50), on 12 May 2017, at 12 noon
UNIVERSITY OF OULU, OULU 2017
Copyright © 2017Acta Univ. Oul. D 1410, 2017
Supervised byProfessor Kaisa Tasanen-MäättäProfessor Markku Timonen
Reviewed byDocent Jaana PaneliusProfessor Sinéad Langan
ISBN 978-952-62-1530-3 (Paperback)ISBN 978-952-62-1531-0 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2017
OpponentDocent Sirkku Peltonen
Försti, Anna-Kaisa, Incidence, mortality, comorbidities, and treatment of bullouspemphigoid in Finland. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; Oulu UniversityHospital; Medical Research Center OuluActa Univ. Oul. D 1410, 2017University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Bullous pemphigoid (BP) is an autoimmune skin disease predominantly found in elderly people,which causes blistering of the skin and severe itching. The incidence of BP reported by previousstudies has varied greatly between 0.05 and 42.8 per 1 million persons per year. Higher incidenceshave been reported in Western Europe and the USA, while countries around the Mediterraneanhave reported lower rates. However, the epidemiology of BP has not previously been studied inany Scandinavian country. The one-year mortality of BP is highly variable with estimates between11% and 41% worldwide. As for comorbidities, the previous studies have shown that BP isassociated with neurological disorders.
The aim of this study was to investigate the incidence and mortality of BP in Finland, to assessthe treatments used for BP, and the potential contribution of systemic glucocorticoid treatment tothe high mortality rate found in BP patients. A further aim was to obtain more specific informationabout the neurological diseases associated with BP, and to clarify the less studied association withpsychiatric disorders. For these purposes, we collected the records of all immunologicallyconfirmed BP patients diagnosed in the Oulu University Hospital between 1985 and 2012, and, fora sub-study III, data for all patients diagnosed with BP in Finnish hospitals between 1987 and2013.
We found that the incidence of BP in Northern Finland has increased over the past two decadesto approximately 27 new BP cases per 1 million persons per year. The one-year mortality of BPpatients is 17%, and the standardized mortality ratio (SMR) is 7.6. Common comorbidities foundin the sample of BP patients were: cardiovascular diseases (76%), neurodegenerative diseases(41%), skin conditions other than BP (37%) and type 2 diabetes (23%). Many neurodegenerativediseases of the central nervous system were associated with BP, as were many psychiatricdisorders. The association was strongest between multiple sclerosis (MS) and BP, with MSpatients having almost a 6-fold higher risk of BP than controls.
The present study reports for the first time the incidence and mortality of BP in Finland, andprovides new information about the association between BP and neurological and psychiatricdisorders.
Keywords: autoimmune bullous diseases, BP180, bullous pemphigoid, collagen XVII,epidemiology, Finland, incidence, mortality, neurological comorbidity, psychiatriccomorbidity, skin diseases, standardized mortality ratio
Försti, Anna-Kaisa, Rakkulaisen pemfigoidin ilmaantuvuus, kuolleisuus,oheissairaudet ja hoito Suomessa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Oulunyliopistollinen sairaala; Medical Research Center OuluActa Univ. Oul. D 1410, 2017Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Rakkulainen pemfigoidi (josta jatkossa käytetään nimitystä pemfigoidi) on autoimmuunisairaus,joka esiintyy yleensä iäkkäillä, ja aiheuttaa ihon rakkulointia ja hankalaa kutinaa. Aiemmissatutkimuksissa pemfigoidin ilmaantuvuus on vaihdellut 0,05:sta 42,8:aan tapaukseen miljoonaaihmistä kohden vuodessa. Ilmaantuvuuden on havaittu olevan korkeampi Länsi-Euroopassa, kuntaas Välimeren ympäristössä ilmaantuvuus on matalampi. Pemfigoidia sairastavien kuolleisuusvuoden kuluessa diagnoosista vaihtelee noin 11-41%:n välillä. Aiemmat tutkimukset ovat myösosoittaneet, että pemfigoidi liittyy neurologisiin sairauksiin. Pemfigoidin epidemiologiaa ei olekuitenkaan tutkittu Suomessa tai muissa Pohjoismaissa.
Tämän tutkimuksen tarkoituksena oli selvittää pemfigoidin ilmaantuvuus ja kuolleisuus Suo-messa, tutkia sen hoitoon käytettyjä lääkkeitä sekä arvioida systeemisen glukokortikoidihoidonosuutta korkeaan kuolleisuuteen. Lisäksi tavoitteena oli saada yksityiskohtaista tietoa pemfigoi-diin liittyvistä neurologisista sairauksista ja selvittää lisää aiemmissa tutkimuksissa ristiriitaisek-si jäänyttä yhteyttä psykiatrisiin sairauksiin. Tätä varten keräsimme tiedot kaikista Oulun yli-opistollisessa sairaalassa diagnosoiduista, immunologisesti varmennetuista pemfigoiditapauksis-ta vuosilta 1985-2012. Kolmannessa osatyössä käytimme kansallista aineistoa, joka sisälsi kaik-kialla Suomessa diagnosoidut pemfigoidia sairastavat potilaat vuosilta 1987-2013.
Pemfigoidin ilmaantuvuus kasvoi seuranta-aikana ollen nykyisin Pohjois-Suomessa noin 27tapausta miljoonaa ihmistä kohden vuodessa. Kuolleisuus vuoden kuluessa diagnoosista oli 17%ja vakioitu kuolleisuussuhde (standardized mortality ratio) 7,6. Yleisiä oheissairauksia pemfigoi-dia sairastavilla olivat sydän- ja verisuonisairaudet (76%), neurodegeneratiiviset sairaudet(41%), muut ihosairaudet (37%) sekä tyypin 2 diabetes (23%). Tutkimuksessa todettiin, ettämonet neurogeneratiiviset sairaudet ja monet psykiatriset sairaudet liittyvät pemfigoidiin. Yhte-ys oli vahvin pesäkekovettumataudin (MS-tauti) ja pemfigoidin välillä, ja MS-tautia sairastavil-la riski sairastua pemfigoidiin oli lähes 6-kertainen verrattuna kontrollipotilaisiin.
Tämä tutkimus on ensimmäinen, joka raportoi pemfigoidin ilmaantuvuuden ja kuolleisuudenSuomessa. Tutkimus antaa lisäksi uutta tietoa pemfigoidin yhteydestä neurologisiin ja psykiatri-siin sairauksiin.
Asiasanat: autoimmuunirakkulatauti, BP180, epidemiologia, ihosairaus, ilmaantuvuus,kollageeni XVII, kuolleisuus, neurologinen oheissairaus, pemfigoidi, psykiatrinenoheissairaus, rakkulainen pemfigoidi, Suomi, vakioitu kuolleisuussuhde
7
Acknowledgements
This study was carried out at the Department of Dermatology and Medical
Research Center Oulu of the Oulu University Hospital and at the University of Oulu
between the years 2010 and 2017. The work was financially supported by the
Medical Research Center Oulu doctoral program, State Research Funding (EVO),
and research grants from The Finnish Dermatological Society, Finnish Medical
Foundation, University of Oulu Grant Fund, and the Emil Aaltonen Foundation.
I am sincerely grateful to both of my supervisors: Professor and the Head of
the Department of Dermatology, Kaisa Tasanen-Määttä, MD, PhD, and Professor
Markku Timonen, MD, PhD, for all their guidance and support, from the very
beginning of my research career to this day. Their enthusiasm for research has given
me energy to continue and complete this project.
I am also deeply grateful to Jari Jokelainen, M.Sc. This research would not
have been possible without his expertise and help in statistical analyses and
designing the studies. I am very thankful to the Deputy Chief Physician of the
Department of Dermatology, Päivi Hägg, MD, PhD, for managing my clinical work
schedule to allow me to focus on research.
I want to acknowledge the pre-examiners of this thesis: Docent Jaana Panelius,
MD, PhD, and Professor Sinéad Langan, MD, PhD for carefully reading my thesis
and giving constructive comments.
I wish to express my gratitude to the co-authors of the third publication for
good advice based on their extensive experience in scientific work and knowledge
in the fields of neurology and psychiatry: Kari Majamaa, MD, PhD, Professor and
the Head of the Department of Neurology; Hanna Ansakorpi, MD, PhD, Specialist
in Neurology; and Allan Seppänen, MD, PhD, the Head of the Department of
Forensic Psychiatry, HUS.
I warmly thank the follow-up group of this study: Professor Jouko Miettunen,
MD, PhD, Saara Kantola, DDS, and Erika Wikström, MD, PhD, for their wise
comments, kind support and open-minded discussions concerning the ups and
downs of scientific work.
I greatly appreciate the help of my brother-in-law, Steve Smith, for his
excellent comments and careful revision of the English language of both the
original publications and this thesis. Many thanks to Seija Leskelä for helping me
with the figures in my thesis and assisting with other projects.
8
I want to thank all of my colleagues at the Department of Dermatology for their
kind consultations when I needed help, for many inspiring discussions concerning
medicine and for many hilarious discussions having nothing to do with medicine.
My warm thanks and hugs go to my friends and their families. « Good friends
help you find important things when you have lost them. Your smile, you hope, and
your courage. » Thank you all for being there and sharing this wonderful life with
me.
I thank my family with all my heart: my parents Maire and Eino, my brother
Jukka and his family, my parents-in-law Aira and Esko, and my sister-in-law Aino
and her family for their love and support and for so many happy moments we have
shared. Special thanks go to both grandparents for taking care of our kids whenever
it has been needed. My deepest gratitude and all my love are owed to my husband
Antti and our lovely children Inkeri and Linnea. Antti, without your understanding
this thesis would not have been possible. I also admire your positive attitude to life.
Inkeri and Linnea, you fill my life with love and laughter and teach me every day
the true enthusiasm for learning and living.
Oulu, 16th March 2017 Anna-Kaisa Försti
9
Abbreviations
ALS amyotrophic lateral sclerosis
BCC basocellular carcinoma
BP bullous pemphigoid
BPAG bullous pemphigoid antigen
BP180 bullous pemphigoid antigen 180
BP230 bullous pemphigoid antigen 230
BPDAI Bullous Pemphigoid Disease Area Index
CD cluster of differentiation, cluster of designation
CI confidence interval
CNS central nervous system
C3 complement 3
DIF direct immunofluorescence microscopy
DPP-4 dipeptidyl peptidase-4
EBA epidermolysis bullosa acquisita
EDF European Dermatology Forum
ELISA enzyme linked immunosorbent assay
HLA human leukocyte antigen
HR hazard ratio
ICD international classification of diseases
IgA immunoglobulin A
IgE immunoglobulin E
IgG immunoglobulin G
IgM immunoglobulin M
IIF indirect immunofluorescence microscopy
IF immunofluorescence
IRR incidence rate ratio
IL interleukin
kDa kilo Dalton
LAD linear immunoglobulin A disease
NaCl sodium chloride
NOHD the Northern Ostrobothnia Hospital District
MMP mucous membrane pemphigoid
MMSE Mini-Mental State Examination
mol mole
MS multiple sclerosis
10
OR odds ratio
PASW Predictive Analytics SoftWare
SD standard deviation
SMR standardized mortality ratio
STATA Data Analysis and Statistical Software
TNF-α tumor necrosis factor alpha
UK the United Kingdom
USA the United States of America
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Original publications
This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Försti A-K, Jokelainen J, Timonen M & Tasanen K (2014) Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol 171(5): 1223-1226.
II Försti A-K, Jokelainen J, Timonen M & Tasanen K (2016) Risk of Death in Bullous Pemphigoid: A Retrospective Database Study in Finland. Acta Derm Venereol 96(6): 758-761.
III Försti AK, Jokelainen J, Ansakorpi H, Seppänen A, Majamaa K, Timonen M, Tasanen K. (2016) Psychiatric and neurological disorders are associated with bullous pemphigoid - a nationwide Finnish Care Register study. Sci Rep 6:37125, doi: 10.1038/srep37125.
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Contents
Abstract
Tiivistelmä
Acknowledgements 7 Abbreviations 9 Original publications 11 Contents 13 1 Introduction 17 2 Review of the literature 19
2.1 General aspects of bullous pemphigoid (BP) .......................................... 19 2.2 Epidemiology of bullous pemphigoid ..................................................... 19
2.2.1 Incidence ...................................................................................... 19 2.2.2 Mortality ....................................................................................... 20 2.2.3 Associated diseases ...................................................................... 21 2.2.4 Predisposing factors ..................................................................... 24
2.3 Clinical presentation and prognosis of bullous pemphigoid ................... 25 2.3.1 Clinical features ............................................................................ 25 2.3.2 Clinical course and prognosis ....................................................... 26
2.4 Other pemphigoid subtypes..................................................................... 26 2.4.1 Mucous membrane pemphigoid ................................................... 27 2.4.2 Pemphigoid gestationis ................................................................. 27 2.4.3 Linear IgA disease ........................................................................ 27 2.4.4 Epidermolysis bullosa acquisita ................................................... 28
2.5 Pathophysiology of bullous pemphigoid ................................................. 28 2.5.1 Hemidesmosomes ......................................................................... 28 2.5.2 Bullous pemphigoid antigens in the skin and
pathomechanisms in bullous pemphigoid .................................... 29 2.5.3 Bullous pemphigoid antigens in other tissues .............................. 30
2.6 Diagnostics of bullous pemphigoid ......................................................... 31 2.6.1 Clinical criteria ............................................................................. 31 2.6.2 Direct immunofluorescence microscopy (DIF) ............................ 31 2.6.3 Indirect immunofluorescence microscopy (IIF) ........................... 32 2.6.4 Enzyme linked immunosorbent assay (ELISA) ........................... 32 2.6.5 Histopathology ............................................................................. 33 2.6.6 Other diagnostic techniques ......................................................... 33
2.7 Treatment of bullous pemphigoid ........................................................... 33
14
2.7.1 Drugs used to treat bullous pemphigoid ....................................... 33 2.7.2 Mechanism of action of glucocorticoid treatment ........................ 35 2.7.3 Side-effects of glucocorticoid treatment ....................................... 36
3 Aims of the study 39 4 Materials and methods 41
4.1 Study populations and databases ............................................................. 41 4.1.1 Northern Ostrobothnia Hospital District study population
(I, II) ............................................................................................. 41 4.1.2 National study population (III) ..................................................... 43
4.2 Diagnostic criteria ................................................................................... 44 4.2.1 Diagnostic criteria in the Northern Ostrobothnia Hospital
District study population (I, II) ..................................................... 44 4.2.2 Diagnostic criteria in the national Care Register for Health
Care study population (III) ........................................................... 45 4.3 Statistical analyses (I, II, III) ................................................................... 45 4.4 Permissions and ethical aspects (I, II, III) ............................................... 47
5 Results 49 5.1 Characteristics of the study populations .................................................. 49
5.1.1 Characteristics of the Northern Ostrobothnia Hospital
District study population (I, II) ..................................................... 49 5.1.2 Characteristics of the national study population (III) ................... 49
5.2 Clinical features of bullous pemphigoid (I) ............................................ 50 5.3 Incidence of bullous pemphigoid (I, III) ................................................. 50 5.4 Mortality of bullous pemphigoid (II) ...................................................... 51
5.4.1 Comorbidities and mortality ......................................................... 51 5.4.2 Concomitant medications and mortality ....................................... 51 5.4.3 Treatment for bullous pemphigoid and mortality ......................... 51
5.5 Association with neurological diseases (III) ........................................... 52 5.6 Association with psychiatric diseases (III) .............................................. 53
6 Discussion 55 6.1 Increasing incidence of bullous pemphigoid in Finland (I, III) ............... 55 6.2 High mortality among bullous pemphigoid patients (II) ......................... 56 6.3 Factors increasing the mortality rate in bullous pemphigoid (II) ............ 57 6.4 Systemic glucocorticoids and mortality (II) ............................................ 58 6.5 Increased risk of bullous pemphigoid in patients with
neurological and psychiatric disorders (III) ............................................ 59
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6.5.1 Pathomechanisms behind the epidemiological association
between bullous pemphigoid and neurological disorders ............. 60 6.6 Strengths and limitations of the study ..................................................... 62 6.7 Future prospects ...................................................................................... 62
7 Conclusions 63 List of references 65 Original publications 75
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1 Introduction
Bullous pemphigoid (BP) is an autoimmune skin disease, which belongs to the
pemphigoid group. BP usually affects elderly people after the 7th decade of life, and
considerably impairs the patient’s quality of life with symptoms like intense
pruritus and blistering of the skin. The diagnosis of BP is confirmed by
immunological investigations, and an evaluation by a dermatologist is needed. In
cases of BP that involve widespread blistering, treatment is generally started in a
dermatologic ward (Di Zenzo et al. 2012, Schmidt & Zillikens 2013).
The mainstream treatment of BP consists of systemic and topical
glucocorticoids. However, systemic glucocorticoids, especially when used in
elderly people, are associated with potentially severe side-effects, like diabetes,
osteoporosis, heart failure, and irritation of the gastric mucosa. Moreover, it is
suspected that the use of systemic glucocorticoids may contribute to the high
mortality rate seen in BP patients (Feliciani et al. 2015, Joly et al. 2002, Venning et al. 2012). However, before the invention of glucocorticoids, the mortality rate of
BP was even higher than now with estimates at 40% (Zillikens 2009).
The idea of this study arose in daily practice in the Department of Dermatology
at the Oulu University Hospital, where we noticed an increase in the number of
new BP patients. By the start of this study in 2010, only one previous study had
reported an increasing incidence of BP (Langan et al. 2008), and there were no
epidemiological data at all for BP in Finland, or even in other Scandinavian
countries. In general, epidemiology is a branch of science that investigates
phenomena related to health and diseases, such as the incidence or mortality of a
disease in different populations. Epidemiology can, for example, study how
common a disease is in a certain population, reveal factors that predispose patients
to particular diseases, or determine causal relations between phenomena, such as
response to treatment. In this study, we wanted to gather epidemiological data on
BP in Finland. The study started with investigations of the incidence of BP in the
Northern Ostrobothnia Hospital District (NOHD), continued with mortality
assessments, and was augmented with an examination of a large, national data set
of more than 4500 BP patients, and their neurological and psychiatric comorbidities.
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19
2 Review of the literature
2.1 General aspects of bullous pemphigoid (BP)
The pemphigoid diseases were first distinguished from another autoimmune skin
disease, pemphigus by their clinical and histopathological features in 1953 (Lever
1953). Nowadays, BP is a well-defined autoimmune blistering skin disease, and the
most common of the pemphigoids. In BP, autoantibodies target the basement
membrane structures between the epidermis and dermis of the skin causing
subepidermal blisters. In pemphigus, blister formation occurs in the upper layer of
the skin, between keratinocytes (Lever 1953, Schmidt & Zillikens 2013).
2.2 Epidemiology of bullous pemphigoid
2.2.1 Incidence
Based on studies around the world, the yearly incidence of BP varies between 0.05
and 42.8 per 1 million inhabitants per year (Alpsoy et al. 2015, Joly et al. 2012,
Langan et al. 2008, Marazza et al. 2009, Uzun et al. 2006). The incidence of BP
was 6.1–6.6 per 1 million persons per year in Germany between 1989 and 1997
(Jung et al. 1999, Zillikens et al. 1995), 12.1 in Switzerland between 2001 and 2002
(Marazza et al. 2009) and 21.7 in France between 2000 and 2005 (Joly et al. 2012),
and the incidence has been reported to have increased in recent years (Bernard et al. 1995, Joly et al. 2012, Langan et al. 2008). A UK study found that the incidence
of BP increased 5-fold over 11 years to 2006 (Langan et al. 2008), whereas in
France the increase was 3-fold over 15 years to 2005 (Bernard et al. 1995, Joly et al. 2012). A recent study from Serbia reported that the incidence of BP increased
0.06 cases per 1 million persons per year over a 20-year time period to 2010
(Milinkovic et al. 2016).
Besides true variation of incidence, other reasons behind notably variable
numbers may include differences in diagnostic criteria used, different age structures
of study populations and differences in the study countries’ healthcare systems
(Langan et al. 2008, Marazza et al. 2009, Naldi et al. 2012). Most of the studies
have used the databases of dermatology departments/clinics – an approach that may
result in underestimation of the incidence of BP through lack of diagnosis of the
mildest cases (Langan et al. 2008). Only one study, by Langan and her coworkers,
20
investigated the incidence of BP based on the general practice database, and
reported the incidence as high as 42.8 new BP cases per 1 million persons per year
in the UK (Langan et al. 2008). However, it is unknown which of the cases captured
by this study were verified by immunological examinations.
While BP is the most common autoimmune bullous disease in Western Europe
and in the USA, countries around the Mediterranean have reported higher
incidences of the other autoimmune blistering skin disease, pemphigus (Alpsoy et al. 2015, Baican et al. 2010, Bastuji-Garin et al. 1995, Chams-Davatchi et al. 2005).
Pemphigus is known to be associated with Jewish origin and certain human
leukocyte antigen (HLA) genotypes, namely HLA-DRB1*04, HLA-DRB1*14,
and HLA-DQB1*05 (Ahmed et al. 1990, Alpsoy et al. 2015, Simon et al. 1980).
In Brazil, there is also an endemic form of pemphigus, called fogo selvagem
(Culton et al. 2008). Differing life expectancies may also play a role in the different
distributions of pemphigus and BP, since BP typically affects older persons than
pemphigus (Alpsoy et al. 2015).
BP is a disease of elderly people occurring mostly after the age of 70 years
(Alpsoy et al. 2015, Joly et al. 2012, Jung et al. 1999, Langan et al. 2008, Marazza et al. 2009). According to the study by Joly and coworkers the incidence of BP in
the 70-year-old or above population is 162 cases per 1 million persons per year, and
among persons aged 85 years or above, as high as 507 per 1 million persons per
year (Joly et al. 2012). Slightly more cases are found in females, the female-male
ratio being 1.1 in Germany (Zillikens et al. 1995), 1.5 in France (Bernard et al. 1995, Joly et al. 2012) and up to 5.1 in Kuwait (Nanda et al. 2004). However,
females are overrepresented in older age groups, which may affect the sex
distribution of BP (Alpsoy et al. 2015), and indeed, in the study by Langan and
coworkers, the adjusted incidence was equal for both sexes (Langan et al. 2008).
2.2.2 Mortality
BP is associated with a high mortality rate: in most of the studies around 20% of
affected individuals die within the first year after the diagnosis, though the range
has varied between 10.8% and 41%. BP patients also die more often than their age-
adjusted counterparts in the general population, with the standardized mortality
ratio (SMR) varying between 1.9 and 9.6. (Brick et al. 2014a, Cai et al. 2013,
Colbert et al. 2004, Gual et al. 2014, Joly et al. 2005b, Joly et al. 2012, Langan et al. 2008, Lee & Kim 2014, Parker et al. 2008, Roujeau et al. 1998, Rzany et al. 2002).
21
Advanced age among BP patients has been associated with increased mortality
by many studies (Cortes et al. 2011, Cortes et al. 2012, Gual et al. 2014, Joly et al. 2005b, Parker et al. 2008, Rzany et al. 2002). A prospective multicenter study in
France examined prognostic factors of BP in a study group of 170 patients, and
found that advanced age and weak general condition were the main factors that
correlated with decreased one-year survival (Joly et al. 2005b). By contrast, the
severity of clinical symptoms did not correlate with mortality (Joly et al. 2005b).
Another multicenter study comprising 369 patients from Germany (Rzany et al. 2002) reported that the main risk factors for death within one year were advanced
age, low serum albumin level, high erythrocyte sedimentation rate and systemic
glucocorticoid dose more than 37 mg per day at discharge. Altogether, the existing
literature indicates that the elevated mortality of BP patients compared with age-
adjusted reference population is probably caused by poor general health, comorbid
diseases, and possibly also by side-effects of immunosuppressive treatment for BP
(Alpsoy et al. 2015, Joly et al. 2002).
2.2.3 Associated diseases
In general, BP patients have many comorbidities due to advanced age (Cai et al. 2013, Gual et al. 2014). Among these, the most frequently reported are
cardiovascular diseases, neurological diseases and diabetes (Cai et al. 2013, Gual et al. 2014, Marazza et al. 2009, Parker et al. 2008). Although an association
between BP and malignancies has been suspected (Chorzelski et al. 1978), recent
studies have not established any such connection (Cai et al. 2015, Jedlickova et al. 2010, Lindelof et al. 1990, Ong et al. 2014).
Neurological comorbidities
Evidence has accumulated to indicate that there exists an association between BP
and neurological disorders (Table 1) (Brick et al. 2014b, Chen et al. 2011b, Langan et al. 2011, Ong et al. 2013, Taghipour et al. 2010). A case-control study of 89 BP
patients, which investigated the association between BP and internal diseases
including diabetes mellitus, neurological diseases, malignant tumors, benign
prostate hyperplasia, hypertension and ischemic heart diseases found that only
neurological diseases were statistically significantly associated with BP
(Jedlickova et al. 2010). Later studies have showed that BP is particularly
associated with stroke, dementia, and Parkinson’s disease (Table 1) (Brick et al.
22
2014b, Chen et al. 2011b, Langan et al. 2011). However, in previous studies, the
types of dementia and cerebrovascular stroke have not been specified. With regard
to temporal relationships in these studies, neurological disorders mostly preceded
BP (Brick et al. 2014b, Chen et al. 2011b, Langan et al. 2011, Taghipour et al. 2010), but only a few studies with conflicting results have indicated whether the
risk of developing neurological disorders is elevated following a diagnosis of BP
(Brick et al. 2014b, Langan et al. 2011, Ong et al. 2014). These findings
demonstrate the need for further investigation into which specific neurological
disorders are associated with BP, the temporal relationships, and possible causality.
In Finland, neurological and psychiatric disorders belonged to the same
medical specialty until 1960, when they were separated to their own entities. In
order to classify disorders, the International Classification of Diseases (ICD) has
been used since 1968 in Finland (Lönnqvist et al. 2009), and already in this 8th
revision of the ICD, neurological and psychiatric disorders were their own entities.
In the currently used ICD 10, the category of neurological diseases includes all
diseases of the central and peripheral nervous systems, some muscle diseases, some
congenital conditions such as cerebral palsy and some diseases of the spinal cord.
The diseases associated with BP by previous studies tend to be disorders that have
so-called neuroinflammatory and neurodegenerative mechanisms, such as
Alzheimer’s disease and Parkinson’s disease (Heneka et al. 2015, Hirsch & Hunot
2009). Neurodegeneration is a process that happens in the central nervous system
(CNS) with a progressive loss of structure or function of neurons, including death
of neurons. Recent studies have found that many inflammatory mechanisms are
linked with neurodegeneration (Chen et al. 2016).
Psychiatric comorbidities
Psychiatry investigates disorders that affect aspects of mental health such as mood,
cognition and behavior. In the ICD 10, psychiatric disorders are named ‘mental and
behavioural disorders’, and the category includes diseases with well-known organic
origins such as alcohol abuse, and diseases with much more heterogeneous
pathogenesis such as schizophrenia, mood disorders, and personality disorders
(Lönnqvist et al. 2009). Neuroinflammatory mechanisms have also been
recognized in these disorders (Bhattacharya et al. 2016, Fanning et al. 2015, Muller et al. 2015)
23
Table 1. The association between bullous pemphigoid and neurological and psychiatric
disorders in previous studies.
Database/
population
n(BP) Years Disorders with a statistically significant
association with bullous pemphigoid
(BP)
Ong, 2013, the UK National Health Service
Information Center
9317 1999-2011 Motor neuron disease
Chen, 2011,
Taiwan
National Health
Insurance Research
Database
1997-2008 Stroke, dementia, Parkinson’s
disease, epilepsy, schizophrenia,
psoriasis
Langan, 2011, the
UK
National, General
practice database
868 1996-2006 Stroke, dementia, Parkinson’s
disease, multiple sclerosis, epilepsy
Stinco, 2005, Italy hospitals in North-East
Italy
238 1995-2000 Neurological disease (Parkinson’s
disease or multiple sclerosis)
Bastuji-Garin,
2011, France
11 hospitals 201 2003-2007 Major cognitive impairment, bedridden
condition, Parkinson’s disease,
unipolar or bipolar disorder
Li, 2013, China 1 hospital 190 1992-2012 Neurological diseases
Taghipour, 2010,
the UK
1 hospital 90 2004-2008 Cerebrovascular disease, dementia
Jedlickova, 2010,
the Czech Republic
2 hospitals 89 1991-2006 Neurological diseases
Brick, 2014b, the
USA
Olmsted County,
Rochester Epidemiology
Project
87 1960-2009 Dementia, Parkinson’s disease
Teixeira, 2014,
Portugal
1 hospital 77 1998-2010 Dementia, stroke, bedridden condition
Casas-de-la-
Asunción, 2014,
Spain
1 hospital 56 2002-2012 Dementia, Parkinson’s disease
Kwan, 2015,
Malaysia
1 hospital 43 2004-2013 Dementia
Foureur, 2001,
France
1 hospital 30 1999-2000 Neurological diseases
Some studies have reported an association between BP and psychiatric diseases
(Table 1), but their results remain controversial (Bastuji-Garin et al. 2011, Chen et al. 2011b, Teixeira et al. 2014). Chen and coworkers showed in a large Taiwanese
study population, that patients with schizophrenia are more likely to develop BP
(Chen et al. 2011b), and in the French study by Bastuji-Garin and coworkers, uni-
and bipolar disorders were independent risk factors for BP (Bastuji-Garin et al.
24
2011). On the contrary, no association was seen between BP and depression in the
study by Teixeira and coworkers (Teixeira et al. 2014).
2.2.4 Predisposing factors
Previous studies have shown that the age-adjusted incidence of BP is increasing
(Brick et al. 2014a, Joly et al. 2012, Langan et al. 2008), but the factors behind this
trend are not known. The statistical association between BP and neurodegenerative
diseases is well recognised, with neurodegenerative diseases mostly preceding BP.
The temporal relationship raises the question as to whether nervous system damage
can trigger an immunological process that leads to the development of BP. However,
any molecular mechanisms behind such a process are unknown (Brick et al. 2014b,
Chen et al. 2011b, Langan et al. 2011, Seppänen 2013).
Medications, such as diuretics, neuroleptics, antidiabetics and tumor necrosis
factor alpha (TNFα) inhibitors as well as vaccines have been suggested to
predispose patients to BP (Oh et al. 2016, Stavropoulos et al. 2014). A French study,
which comprised 201 BP patients, found an association between BP and the use of
spironolactone or phenothiazine psycholeptics (Bastuji-Garin et al. 2011). Another
study from the UK reported an association between BP and loop diuretics (Lloyd-
Lavery et al. 2013). Increasing numbers of case reports have linked BP with the
use of dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”), which are common in
the treatment of diabetes, but this association needs to be further investigated
(Stavropoulos et al. 2014). Interestingly, a Japanese study group reported that BP
patients using DPP-4 inhibitors were more likely to have atypical BP, characterized
by a non-inflammatory appearance of BP, and autoantibodies that target the mid-
portion of the bullous pemphigoid antigen 180 (BP180, also known as collagen
XVII or BP antigen 2 [BPAG2]), but not the NC16A domain as is found in typical
BP (Izumi et al. 2016).
In some cases, physical triggers such as ultraviolet light, radiation therapy, and
trauma have been thought to induce BP (Lo Schiavo et al. 2013). Genetic
susceptibility seems to be of less importance in BP than in pemphigus. Furthermore,
there is not such variation in the incidence of BP according to geographic area or
ethnic origin, as in pemphigus (Alpsoy et al. 2015). Regardless, an association
between BP and certain HLA genotypes has been reported. HLA genotypes, in
general, play a key role in genetic predisposing factors in autoimmunity because of
their role in antigen presentation (Lo Schiavo et al. 2013). The HLA-DQB1*0301
allele is associated with enhanced susceptibility to BP among Caucasians (Delgado
25
et al. 1996), as are HLA-DRB1*04 and DRB1*1101 in Japanese people (Okazaki et al. 2000). Interestingly, HLA-DRB1*04 has also been associated with
pemphigus, especially in Ashkenazi Jewish patients (Ahmed et al. 1990).
2.3 Clinical presentation and prognosis of bullous pemphigoid
2.3.1 Clinical features
BP is characterized by subepidermal, tense blisters and erythema which turn into
erosions and crusts within days (Fig. 1).
Fig. 1. Widespread blistering end erythema on the limbs of a bullous pemphigoid
patient (Department of Dermatology, Oulu University Hospital).
Blisters usually appear on the trunk and proximal flexural sites of the limbs. Intense
pruritus is typical of BP, and it can precede blisters by several weeks or even months,
sometimes occurring with atypical skin lesions like excoriations, eczema, papular
or urticarial lesions (Di Zenzo et al. 2012, Schmidt & Zillikens 2013). In up to 20%
of cases, the only lesions seen at the time of BP diagnosis are atypical and without
26
blistering (Di Zenzo et al. 2012). Approximately 10–20% of BP patients have
mucous membrane involvement, usually in the oral cavity (Nishie 2014, Schmidt
& Zillikens 2013). A clinical scoring system, the BP Disease Area Index (BPDAI)
has been developed by an international panel of experts as a tool for the objective
evaluation of BP symptom severity (Murrell et al. 2012).
2.3.2 Clinical course and prognosis
BP appears to be a chronic disease with the possibility of relapse after successful
treatment (Di Zenzo et al. 2012), and, as described above, it carries a high mortality
rate. Clinical symptoms include severe pruritus and in many cases widespread skin
erosions, which can cause pain, disturb sleep and remarkably decrease the patient’s
quality of life. Few studies have characterized the clinical course of BP. In a UK
study conducted among 82 BP patients between 1975 and 1988, the disease lasted
from nine weeks to 17 years with median treatment time of approximately two
years (Venning & Wojnarowska 1992). Another study comprising 118 BP patients
from France investigated the risk of relapse within one year of treatment cessation,
and found, that high titers of BP180 identified by enzyme-linked immunosorbent
assay (ELISA) examination in patients in clinical remission predicted relapse with
a high positive predictive value (91%) (Bernard et al. 2009). However, at the time
of diagnosis, the prognosis of an individual patient is difficult to predict.
2.4 Other pemphigoid subtypes
BP is the most common subtype of the pemphigoid diseases, the other major
subtypes being mucous membrane pemphigoid (MMP), pemphigoid gestationis,
linear immunoglobulin A (IgA) disease (LAD), and epidermolysis bullosa acquisita
(EBA). Anti-p200 (anti-laminin γ1) pemphigoid and lichen planus pemphigoides
are rare types with fewer than 100 reports of each worldwide. In BP, pemphigoid
gestationis and in linear IgA disease, the main autoantigen is BP180 while other
proteins can also serve as autoantigens in other pemphigoid types. The different
types cannot be diagnosed by clinical appearance alone, hence, diagnostic
investigations are needed (Schmidt & Zillikens 2013).
27
2.4.1 Mucous membrane pemphigoid
MMP is rarer than BP with an incidence between 1.3 and 2.0 per 1 million person-
years (Bernard et al. 1995, Bertram et al. 2009). Earlier, the term cicatricial
pemphigoid was used as a synonym for MMP, but nowadays, it refers to a rare
variant in which mucosal symptoms are scarce, and skin lesions heal by scarring
(Schmidt & Zillikens 2013). In MMP, symptoms predominantly localize to mucosal
surfaces, most often to the oral cavity or conjunctiva, and the severity of the disease
is highly variable. The autoantigens for MMP are heterogeneous and include BP180,
bullous pemphigoid antigen 230 (BP230 or BP antigen 1, BPAG1), laminin 332,
α6β4 integrin, and collagen VII (Rashid et al. 2006, Schmidt & Zillikens 2013).
2.4.2 Pemphigoid gestationis
Pemphigoid gestationis occurs mostly in the 2nd or 3rd trimester of pregnancy, and
typically starts with intense pruritus around the navel. Skin symptoms vary, and
include erythema, papules, urticarial plaques or erythema multiforme-like target
lesions, followed by blisters after some weeks (Ambros-Rudolph 2011, Huilaja et al. 2014, Sadik et al. 2016). Most (approximately 75%) patients experience
worsening of symptoms during delivery, but in the majority of cases, the disease is
limited to six months thereafter. In pemphigoid gestationis, as in BP, the major
autoantigen is the NC16A domain of BP180 (Huilaja et al. 2014, Sadik et al. 2016,
Schmidt & Zillikens 2013).
2.4.3 Linear IgA disease
The reported incidence of LAD varies between 0.26 and 1.0 per 1 million persons
per year (Bernard et al. 1995, Bertram et al. 2009, Wong & Chua 2002). LAD has
two peaks of onset: it is the most common pemphigoid disease in children, mostly
occurring before the age of five years. Its other peak in incidence is seen in the
population aged over 60 years (Schmidt & Zillikens 2013). Clinical features typical
of LAD include annular lesions with blisters, and consistently with other
pemphigoid types, urticarial or eczematous lesions can also appear. Mucosal
involvement is seen in about 70% of cases (Schmidt & Zillikens 2013). LAD
autoantibodies are mainly of the IgA type, and target BP180 (Marinkovich et al. 1996, Zillikens et al. 1999).
28
2.4.4 Epidermolysis bullosa acquisita
In contrast to the other major pemphigoid types, the autoantibodies in EBA do not
target BP180, but collagen VII, locating in lower basement membrane zone (Fig.
2) (Woodley et al. 1984, Woodley et al. 1988). Its clinical appearance can vary, and
based on its manifestation, it can be classified into two subtypes. The classical
mechanobullous EBA subtype manifests as blisters and erosions following friction
of the skin, whereas the inflammatory type more closely resembles BP or MMP. In
the mechanobullous type, skin lesions heal with scarring and milia formation.
Mucosal lesions occur in approximately half of the cases in each subtype (Chen et al. 2012, Schmidt & Zillikens 2013). The incidence of EBA in Europe is
approximately 0.2–0.5 per 1 million person-years (Bernard et al. 1995, Bertram et al. 2009).
2.5 Pathophysiology of bullous pemphigoid
2.5.1 Hemidesmosomes
Hemidesmosomes are adhesion structures in the skin, which bind epidermal basal
cells to the underlying extracellular matrix. The extracellular matrix beneath the
layer of basal keratinocytes forms a structure called the basement membrane, which
binds the epidermis to the dermis. The basement membrane consists of two layers:
the lamina lucida and the lamina densa (Fig. 2). Hemidesmosomes are comprised
of many molecules including BP180, BP230, plectin and α6β4 integrin, and they
interact with several other molecules in the basement membrane zone including
laminin 111 (which includes the laminin γ1 chain), laminin 332 and collagens IV
and VII (Fig. 2) (Goletz et al. 2014, Nishie 2014, Schmidt & Zillikens 2013). In all
pemphigoid diseases, autoantibodies are directed at the structural molecules of
hemidesmosomes or adjacent proteins causing breakage of the adhesion between
basal cells and the extracellular matrix and, consequently, subepidermal blisters
(Nishie 2014, Schmidt & Zillikens 2013).
29
Fig. 2. The structure of the dermal-epidermal junction and hemidesmosome (based on
personal communications with professor Bruckner-Tuderman).
2.5.2 Bullous pemphigoid antigens in the skin and
pathomechanisms in bullous pemphigoid
In BP, the major autoantigen is BP180, more specifically the extracellular 16th non-
collagenous (NC16A) domain of BP180 (Fig.2). Autoantibodies against another
protein, BP230 and autoantibodies against other parts of BP180 aside from the
NC16A domain are also often involved, but their pathogenic importance in BP is
somewhat unclear (Di Zenzo et al. 2008, Diaz et al. 1990, Jordon et al. 1967, Labib et al. 1986, Nishie 2014, Schmidt & Zillikens 2013).
Typically, the autoantibodies to NC16A are of the immunoglobulin G (IgG)
type, but immunoglobulin E (IgE) and IgA antibodies are also sometimes found
(Nishie 2014, Schmidt & Zillikens 2013, Yayli et al. 2011). The pathogenic role of
IgG antibodies has been demonstrated in mouse models (Liu et al. 1993), and titers
correlate with clinical disease activity (Hofmann et al. 2002). The presence of IgE
autoantibodies has been associated with more severe phenotypes and extensive skin
lesions (Dopp et al. 2000, Hofmann et al. 2002). Blister formation is finally
30
mediated by complement activation and the inflammatory mechanisms that follow.
However, a complement-independent pathway can also be involved (Fig. 3) (Nishie
2014). Recent studies have also shown that NC16A-reactive CD4+ T-cells may
have a role in blister formation, probably in certain genetically susceptible
individuals. Nevertheless, the reasons behind the onset of autoimmune process and
the formation of autoantibodies are not known (Nishie 2014, Schmidt & Zillikens
2013).
Fig. 3. Potential mechanisms of blister formation in bullous pemphigoid (modified from
Lo Schiavo et al. 2013, Nishie 2014)
2.5.3 Bullous pemphigoid antigens in other tissues
As well as in the skin, BP180 is also expressed in the CNS, gastrointestinal tract,
urinary bladder, heart, eye, placenta, and amniotic membranes (Aho & Uitto 1999,
Claudepierre et al. 2005, Huilaja et al. 2008, Seppänen et al. 2006, Van den Bergh
& Giudice 2003) In the CNS, it is predominantly located in the soma and proximal
axons of neurons. The areas of strong expression of BP180 are the deepest,
ganglionic layer of the cerebral cortex, the hippocampus, and many nuclei
(hypoglossal nucleus, oculomotor nucleus, nucleus basalis of Meynert, supraoptic
31
nucleus and subthalamic nuclei) (Seppänen et al. 2006, Seppänen 2013). As
epidemiological studies have affirmed statistical association between BP and
neurological disorders (Brick et al. 2014b, Chen et al. 2011b, Langan et al. 2011,
Ong et al. 2013), an interesting question has been posed, as to whether
autoimmunization against BP180 would be involved in the pathogenesis of
neurological disorders (Seppänen 2013).
BP230 has also been detected in tissues other than skin including central and
peripheral nervous systems, and cardiac and skeletal muscle. This protein exists in
many isoforms, and the epithelial (BPAG1-e) and neuronal (BPAG1-a) isoforms,
and other variants have differences in their localization and molecular structure
(Chen et al. 2011a, Kunzli et al. 2016, Laffitte et al. 2005). Regardless of these
differences, BP230 is a potential shared target of antigen response in the skin and
CNS (Seppänen 2013).
2.6 Diagnostics of bullous pemphigoid
2.6.1 Clinical criteria
In clinically typical cases, when widespread tense blisters are seen on eczematous
skin of an elderly person who suffers from intensive itching, the diagnosis of BP is
easy, and can be confirmed by direct immunofluorescence microscopy (DIF)
examination of a perilesional skin biopsy (Di Zenzo et al. 2012, Vaillant et al. 1998).
A study by the French Bullous Study Group showed that, in cases with positive DIF
findings, i.e. linear deposits of IgG or complement 3 (C3) along the basement
membrane zone, three of the following four clinical features are enough to make a
diagnosis of BP with high sensitivity (90%) and specificity (83%): 1) age higher
than 70 years 2) absence of atrophic scars 3) absence of mucosal involvement 4)
absence of head and neck skin involvement (Di Zenzo et al. 2012, Vaillant et al. 1998). In atypical cases, in which blisters are not seen, and the appearance of the
skin is e.g. urticarial or eczematous, or when just intense itching is present,
laboratory investigations are of greater importance (Di Zenzo et al. 2012).
2.6.2 Direct immunofluorescence microscopy (DIF)
When clinical features suggest BP, DIF is the gold standard and the most sensitive
(91%) and a very specific (98%) diagnostic test (Sardy et al. 2013). In this
32
investigation, a skin biopsy is taken from healthy looking skin near blisters. The
sample must be snap frozen or placed in a suitable transport medium, otherwise
immunoreactants may rapidly degrade (Mihai & Sitaru 2007). Typically, DIF
reveals linear deposits of IgG or C3, or both, along the basement membrane zone,
but weaker linear IgA or IgE staining can also be involved. In BP, linear
fluorescence seems n-serrated while in EBA the pattern is u-serrated (Di Zenzo et al. 2012, Schmidt & Zillikens 2013). For more accurate diagnostics, DIF can also
be performed using the so-called salt-split skin technique (Sardy et al. 2013). In
this method, after incubating the skin biopsy with 1 mol/l sodium chloride (NaCl)
solution, the epidermis and dermis are separated, and antibodies are seen either in
the epidermal (roof of the blister) or dermal (base of the blister) side of the artificial
blister. In BP, autoantibodies attach to the epidermal side, while in some other
pemphigoids, like EBA, antibodies are seen in the base (Di Zenzo et al. 2012).
2.6.3 Indirect immunofluorescence microscopy (IIF)
In an IIF examination, IgG autoantibodies from a BP patient’s serum are seen to
bind to the basement membrane zone of a substrate, for example monkey or rabbit
esophagus tissue. The sensitivity of this investigation varies between 60–80%,
although greater sensitivity can be achieved by using salt-split skin as a substrate
(Di Zenzo et al. 2012, Sardy et al. 2013). Other circulating antibodies, like IgA,
IgE and IgM, can also be searched for using this technique (Di Zenzo et al. 2012).
2.6.4 Enzyme linked immunosorbent assay (ELISA)
An ELISA can detect different parts of BP180, such as the most important BP
autoantigen, the NC16A domain, using recombinant protein techniques. The
NC16A ELISA investigation is commercially available, and provides a highly
sensitive (70–98%) and specific (98%) test for BP diagnostics (Di Zenzo et al. 2012,
Schmidt & Zillikens 2013, Tampoia et al. 2012). Combining this with another
commercial ELISA for BP230 raises sensitivity, but the BP230 assay alone is not
recommended in the diagnostics of BP, since its sensitivity when used alone is 60–
70% (Di Zenzo et al. 2012, Schmidt & Zillikens 2013). A high concentration of
anti-BP180 NC16A antibodies in serum also correlates with a high level of disease
activity (Hofmann et al. 2002), and an elevated risk of relapse after discontinuation
of treatment (Bernard et al. 2009, Schmidt & Zillikens 2013, Tampoia et al. 2012).
All the same, the NC16A ELISA is not able to detect BP in patients who express
33
autoantibodies to regions of BP180 other than the NC16A domain (Nishie 2014,
Schmidt & Zillikens 2013).
2.6.5 Histopathology
Light microscopy of a BP affected skin biopsy cannot differentiate BP from other
types of pemphigoid, and is thus an additional investigation. However,
characteristic findings are subepidermal splitting and the presence of dermal
inflammatory cells, particularly eosinophils. Also other inflammatory cells
including lymphocytes and neutrophils can be involved (Di Zenzo et al. 2012,
Schmidt & Zillikens 2013).
2.6.6 Other diagnostic techniques
As well as ELISA, immunoblotting and immunoprecipitation techniques are also
used to investigate the exact molecular target of autoantibodies. This allows the
detection of different antigens in different types of pemphigoids, for example
laminin γ1, a 200 kilodalton (kDa) glycoprotein, in anti-laminin γ1 pemphigoid
(Dainichi et al. 2009). However, as ELISA is much easier to carry out, it has mostly
replaced immunoblotting (Di Zenzo et al. 2012).
2.7 Treatment of bullous pemphigoid
2.7.1 Drugs used to treat bullous pemphigoid
There have been few prospective, controlled studies of the treatment of BP
(Kirtschig et al. 2010). However, both the British Association of Dermatologists
and the European Dermatology Forum (EDF) have published guidelines for its
management (Feliciani et al. 2015, Venning et al. 2012). There are no official
guidelines in Finland, but clinical practices broadly follow the aforementioned
guidelines.
According to the British Association of Dermatologists and the EDF
guidelines, systemic corticosteroids are the best established treatment for BP, and
starting doses between 0.5 and 0.75 mg/kg/day are recommended (Feliciani et al. 2015, Kirtschig et al. 2010, Venning et al. 2012). Doses higher than 0.75 mg/kg do
not usually give additional benefit, and the adverse effects of high doses of systemic
34
corticosteroids are well recognized (Kirtschig et al. 2010). Very potent topical
corticosteroids are also effective and safe in extensive BP (Joly et al. 2002), but
their use may be limited by practical factors such as cost and, in elderly patients,
lack of mobility limiting the body sites to which cream may be self-applied
(Feliciani et al. 2015, Kirtschig et al. 2010, Venning et al. 2012). Topical
corticosteroids milder than clobetasol propionate 0.05% are also recommended for
the treatment of cases with mild and localized symptoms (Joly et al. 2002, Kirtschig et al. 2010, Terra et al. 2014, Venning et al. 2012). Prospective, controlled studies
of treatment options are needed, and currently a randomized, controlled trial is
underway in the UK and Germany, comparing the safety and efficacy of
doxycycline and systemic prednisolone as first-line treatment of BP (Chalmers et al. 2015).
In severe BP that does not respond to oral corticosteroids, many anti-
inflammatory and immunosuppressive drugs have been used in order to achieve
remission, and to reduce corticosteroid doses. In a French study, 100 patients with
extensive BP were randomized to receive prednisolone 1 mg/kg/day, prednisolone
1 mg/kg/day together with azathioprine from 100 to 150 mg/day, or prednisolone 1
mg/kg/day together with four rounds of large-volume plasmapheresis during the
first 2 weeks (Guillaume et al. 1993). No differences were seen between groups in
terms of the proportion of patients achieving complete remission at day 28 or at 6
months. However, severe complications were more common in the azathioprine
group (Guillaume et al. 1993). Another randomized, controlled study comprised 25
BP patients who were treated with prednisone, either alone (30–80 mg/day), or in
combination with azathioprine 2.5 mg/kg/day (Burton et al. 1978). This three-year
study reported a 45% reduction in the cumulative dose of prednisone in the group
which received azathioprine, with minimal additional side effects (Burton et al. 1978). A more recent study compared the efficacy and safety of
methylprednisolone 0.5 mg/kg/day combined with either azathioprine 2 mg/kg/day
or mycophenolate mofetil 2 g/day (Beissert et al. 2007). The primary outcome was
complete remission, which was achieved by all patients in both groups. However,
remission was induced sooner in the azathioprine group. Hepatotoxicity was more
common in the azathioprine group, but more infections occurred in the
mycophenolate mofetil group (Beissert et al. 2007, Bystryn 2008).
One small randomized trial compared the effects of prednisone 40–80 mg/day
with those of tetracycline 2 g/day plus nicotinamide 1500 mg/day (Fivenson et al. 1994). In this study, there was no statistically significant difference in the treatment
response between these two treatment protocols, but adverse reactions were fewer
35
in the tetracycline-nicotinamide group. However, the small number of patients in
this study limits the conclusions that may be drawn (Fivenson et al. 1994).
Overall, there is little evidence for the benefits of adjuvant therapies. Studies
have reported no additional benefit in disease control of adjuvant azathioprine,
mycophenolate mofetil or plasma exchange when compared with prednisolone
monotherapy. Neither was tetracycline together with nicotinamide more effective
than prednisone (Beissert et al. 2007, Burton et al. 1978, Fivenson et al. 1994,
Guillaume et al. 1993, Kirtschig et al. 2010, Venning et al. 2012). However, small
populations or methodological issues limit the conclusions that can be drawn from
many of these studies (Kirtschig et al. 2010). Methotrexate, dapsone,
cyclofosfamide, cyclosporin, rituximab, chlorambucil and intravenous
immunoglobulin are other examples of therapies that have been used for the
treatment of BP, but without supporting evidence from clinical trials (Venning et al. 2012).
The use of therapies for BP varies widely in Europe. In Denmark, azathioprine
is frequently used in combination with oral glucocorticoids (Kibsgaard et al. 2014),
while in Sweden, methotrexate monotherapy is common (Kjellman et al. 2008). In
France, topical treatment with very potent corticosteroid cream (0.05% clobetasol
propionate) is preferred to systemic treatment (Joly et al. 2002). However, each
patient should be treated individually taking into account factors such as
comorbidities, other medications, the patient’s own opinion, and practical factors.
2.7.2 Mechanism of action of glucocorticoid treatment
Glucocorticoids, administered both topically and systemically, are widely used in
BP and in other skin diseases (Jackson et al. 2007). In cells, the effects of
glucocorticoids are mediated via glucocorticoid receptors, which are expressed in
practically all human cell types. After binding to the intracytoplasmic
glucocorticoid receptor, the resulting complex is transferred to the nucleus, where
it binds to steroid-responsive genes (Jackson et al. 2007, Rhen & Cidlowski 2005).
By various mechanisms, glucocorticoids suppress the production of many
inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukins
(e.g. IL-1, IL-2, IL-6 and IL-8). Glucocorticoids also broadly affect the distribution
and activity of all the body’s inflammatory cells. The proliferation of T-
lymphocytes is inhibited, while B-lymphocytes are affected only by higher doses
of glucocorticoids. Glucocorticoids also lower the numbers of circulating
eosinophils and monocyte-macrophage-line cells. In turn, circulating neutrophil
36
numbers increase because of accelerated release from the bone marrow (Jackson et al. 2007).
2.7.3 Side-effects of glucocorticoid treatment
Short-term glucocorticoid therapy is usually quite well tolerated, but prolonged or
high-dose use is associated with many side-effects, especially in elderly people
(Table 2).
Table 2. Side-effects of high-dose or prolonged glucocorticoid therapy (modified from
Jackson et al. 2007, Rhen & Cidlowski 2005).
Tissue/system Side effecs
Adrenal gland Adrenal atrophy, withdrawal syndrome
Cardiovascular system Hypertension, edema, thrombosis, vasculitis
Metabolic Hyperglycemia, dyslipidemia, obesity, hypocalcemia,
hypokalemia
Nervous system
Changes in behavior, cognition, memory, and mood.
Peripheral neuropathy
Gastrointestinal tract
Gastrointestinal bleeding, pancreatitis, peptic ulcer,
esophagitis
Immune system
Broad immunosuppression, activation of latent
viruses
Skin
Atrophy, purpura, hirsutism, hyperpigmentation,
acne, acneiform eruptions, infections, delayed
wound healing
Musculoskeletal system
Osteoporosis, bone necrosis, muscle atrophy,
growth retardation
Eyes
Cataracts, glaucoma
Reproductive system Delayed puberty, fetal growth retardation,
hypogonadism, amenorrhea
The most prevalent and obvious side-effects are osteoporosis and hyperglycemia.
In bone, glucocorticoids induce apoptosis of osteoblasts and increase the activity
of osteoclasts resulting in significant demineralization, and consequently, increased
risk of bone fractures. Osteonecrosis and myopathy are also known to be associated
with glucocorticoid treatment (Jackson et al. 2007).
The development of hyperglycemia is common during prolonged
glucocorticoid treatment, especially, when there is pre-existing glucose intolerance.
37
Glucocorticoids elevate blood glucose by enhancing hepatic gluconeogenesis, and
decreasing peripheral glucose uptake in muscles (Jackson et al. 2007). They also
cause hyperlipidemia, most commonly the elevation of triglycerides, and
hypertension which may result from renal sodium retention (Jackson et al. 2007,
Rhen & Cidlowski 2005).
Since glucocorticoids act on BP via various immunosuppressive mechanisms,
they carry an elevated risk for many bacterial, viral, fungal, and parasite infections
(Jackson et al. 2007). Glucocorticoids also suppress the symptoms of infections,
like fever, making them more difficult to recognize. Fungal and cutaneous
staphylococcal infections are commonly seen in patients receiving glucocorticoid
therapy. A potentially life-threatening infection related generally to
immunosuppression and also to glucocorticoid treatment is Pneumocystis jiroveci
(formerly known as Pneumocystis carinii) pneumonia. Coexisting hyperglycemia,
for its part, makes patients even more susceptible to infections (Jackson et al. 2007).
Other relatively common side-effects of glucocorticoid therapy include
hypothalamus-pituitary gland-adrenal gland (HPA axis) suppression,
gastrointestinal irritation, acne, cataracts and changes in mood, behavior or
cognition (Jackson et al. 2007, Rhen & Cidlowski 2005). Individual patient
characteristics affect the risk of side-effects: postmenopausal women are at great
risk of osteoporosis, as are patients with rheumatoid arthritis. Any condition that
causes hypoalbuminemia leads to an increased free fraction of glucocorticoids, i.e.
an increase in the amount the drug biologically active, and thereby, increased
toxicity. Smoking, alcohol intake and the consumption of many drugs, for their part,
increase the risk for peptic ulcer disease (Jackson et al. 2007). All things considered,
BP patients, who are usually elderly people, are prone to the side-effects of
glucocorticoids, and it has been suggested that the heightened mortality seen in BP
patients may be partly due to the medications used to treat the condition (Feliciani et al. 2015).
38
39
3 Aims of the study
Given the lack of information previously reported in Finland or other Scandinavian
countries, this study was designed to obtain information about the epidemiology,
incidence and mortality of BP in Finland, and its comorbidities. The specific aims
of the publications I–III were as follows:
I To determine the incidence of BP in the NOHD and to document the changes
in incidence over time.
II To investigate the mortality and comorbidities of BP patients in the NOHD,
medications used to treat BP, and possible associations between treatment and
mortality.
III To investigate the association between BP and neurological and psychiatric
disorders, temporal causality between these diseases, and the incidence of BP
in the whole of Finland.
40
41
4 Materials and methods
4.1 Study populations and databases
4.1.1 Northern Ostrobothnia Hospital District study population (I, II)
The study population of the first and the second publications consists of BP patients
living in the NOHD, which locates in Northern Finland. The centre of the NOHD
is the Oulu University Hospital, which has the only department of dermatology in
the area, and the only department of pathology that performs immunofluorescence
diagnostics of skin biopsies.
The study population of the first publication covers all BP patients diagnosed
in the outpatient clinic or ward of the Oulu University Hospital between 1st Jan
1985 and 31st Dec 2009. The second publication extended this study period to
include the years 2010–2012. The study populations in both publications comprised
of records retrieved by a search of the Oulu University Hospital database using
codes from the ICD versions 8–10 (code 694 in ICD 8, 694.5 and 694.6 in ICD 9,
and L12 in ICD 10). The initial BP diagnoses in each case retrieved were further
evaluated against the diagnostic criteria used in this study. ICD 8, 9, and 10 were
used in Finland between the years 1968 and 1986, 1987 and 1995, and from the
year 1996 onwards, respectively (Statistics Finland, http://www.tilastokeskus.fi)
(Lönnqvist et al. 2009).
Variables in the Northern Ostrobothnia Hospital District study population
The evaluation of the patient records was done by one researcher (A-K.F.), and a
structured form for every patient was used to collect data about diagnostic tests,
duration of symptoms, mucosal involvement, treatments used for BP, other
medications, comorbidities before and after the diagnosis of BP, and date of death
(Fig. 4). If the date of death was not available in a patient’s hospital records, it was
obtained from the Local Office of Northern Finland or from Statistics Finland.
Every treatment used for BP was recorded with the data on the duration of each
medication, and the order in which they were used. The starting dose of
prednisolone was registered as milligrams (mg).
Diagnoses preceding BP and comorbidities were recorded as of interest if they
could be classified as one of the following categories: autoimmune disease,
42
Fig. 4. Data collection form used in the NOHD population (translated into English).
43
malignancy, type 2 diabetes, cardiovascular disease, neurodegenerative disease or
skin condition other than BP. Autoimmune diseases included diseases defined in a
study conducted in Denmark (Eaton et al. 2010), except for autoimmune skin
diseases, which were registered as ‘other skin condition’. Multiple sclerosis, was
recorded as a neurodegenerative disease, although being also of autoimmune origin.
Neurodegenerative diseases included e.g. cerebrovascular strokes, dementias and
Parkinson’s disease, whereas epilepsy and congenital conditions were excluded.
The cardiovascular disease category included all kinds of cardiac and blood vessel
diseases. The comorbidities registered following the diagnosis of BP included
severe infections, osteoporosis, type 2 diabetes, peptic ulcer, psychiatric symptoms,
cataracts, and glaucoma. Diagnoses preceding BP and comorbidities were included,
if the disease was mentioned in patient’s record. The verification of diagnoses was
not possible.
Groupings used in the Northern Ostrobothnia Hospital District study population
In the second publication, the risk of death in BP patients was analyzed in three
different treatment groups. The groups were formed according to the expected
prognosis for each group. Group one consisted of BP patients treated with oral
prednisolone together with topical corticosteroids. Group two was formed of
patients treated with topical corticosteroids, with or without oral tetracycline.
Group three comprised patients who received both oral prednisolone and an
adjuvant immunosuppressant (azathioprine or methotrexate). Patients were not
excluded from group three if they had used topical corticosteroids and/or
tetracycline and/or dapsone, before prednisolone was initiated.
4.1.2 National study population (III)
The study population of the third publication was obtained from the Finnish Care
Register for Health Care (formerly named the Finnish Hospital Discharge Register)
maintained by the National Institute of Health and Welfare
(https://www.thl.fi/en/web/thlfi-en). The register covers all Finnish hospitals
managed by local authorities, municipal federations and central government as well
as the largest private hospitals, and contains, for example, the identification number
of the patient and hospital, primary diagnosis together with three subsidiary
diagnoses, and duration of hospital stay. Outpatient visits are included from 1998
44
onwards. Studies evaluating the validity of Finnish registries and comparing
registry data with patient records, have confirmed that the coverage and accuracy
of the Care Register are well-suited for epidemiological research (Sund 2012).
However, most of the validation studies have investigated vascular diseases, mental
disorders or injuries, and the number of skin diseases in validation studies is small
(Aro et al. 1990, Sund 2012).
The third publication covered the study period between 1st Jan 1987 and 31st Dec
2013, and thus, ICD 9 and 10 codes for BP were used (6945A and 6945B in ICD 9,
and L12.0 in ICD 10). The control population consisted of patients with
basocellular carcinoma (BCC; ICD 9 codes 1730A–1739A and ICD 10 codes
C44.01, C44.11, C44.21, C44.31, C44.41, C44.51, C44.61, C44.71, C44.81,
C44.91), because it is a common diagnosis, not inflammatory of origin, and BCC
patients tend to be of a similar age to the BP population. Primary and subsidiary
diagnoses were gathered for BP patients and for controls from the Care Register for
Health Care. A large range of central and peripheral nervous system diseases, and
psychiatric disorders were included in the study (please see III, Table 1). Dementias
were classified as CNS diseases, although they belong to the category of mental
and behavioural disorders in the ICD 10. Diseases with known non-
neuroinflammatory origins, such as congenital conditions, epilepsy, and organic
disorders resulting from the use of drugs or psychoactive substances, were excluded.
4.2 Diagnostic criteria
4.2.1 Diagnostic criteria in the Northern Ostrobothnia Hospital
District study population (I, II)
The diagnosis of suspected BP patients identified from the Oulu University
Hospital patient records was evaluated with the following criteria: clinical features,
histopathological and immunopathological examination of skin biopsies, and
serological assays including IIF and BP180 ELISA. In publications I and II, the
diagnosis of BP was considered to be verified if clinical features were appropriate
for BP and either the DIF or IIF was positive. Patients with only clinical features
characteristic of BP were excluded, as were patients with only positive histology
and/or positive BP180 ELISA.
For a positive BP diagnosis, these studies followed the guidelines of the British
Association of Dermatologists for the management of bullous pemphigoid,
45
(Venning et al. 2012). Clinical features: non-scarring blisters and/or erosions of the
skin with or without mucous membrane lesions. In atypical BP cases: eczematous
or urticarial, and itchy lesions of the skin without blistering, evaluated by a
dermatologist. Histopathologic examination: subepidermal blister. DIF: linear
deposits of IgG and/or C3 along the basement membrane zone. IIF: circulating
autoantibodies in the serum against the basement membrane zone detected by IIF
performed on frozen sections of monkey or rabbit esophagus tissue. ELISA:
circulating autoantibodies to recombinant human BP180 protein’s NC16A domain.
Histopathological examinations and DIFs were performed at the Department of
Pathology, the Oulu University Hospital; IIFs and ELISAs were performed in the
HUSLAB, Helsinki (the manufacturer of the BP180 ELISA kit: Mbl, Medical &
Biological laboratories Co., LTD, Japan). ELISA assays have been taken in the
Oulu University Hospital since 2002 and are analysed in the HUSLAB. The BP180
ELISA kit did not change over the study period.
4.2.2 Diagnostic criteria in the national Care Register for Health Care
study population (III)
The third publication was a register based study, and immunological validation of
BP diagnoses was not possible. As well as a search hit based on the relevant ICD
codes, an age of 40 years or above was required, since BP rarely affects younger
individuals, and the possibility of false diagnoses was considered to be high in
younger age groups. When analysing comorbid diseases, only primary psychiatric
diagnoses made in a specialized care setting were included in order to ensure the
validity of psychiatric diagnoses.
4.3 Statistical analyses (I, II, III)
Statistical analyses were carried out using STATA (Data Analysis and Statistical
Software, MP 11.2 StataCorp LP, College Station, TX 77845, USA) and PASW
(Predictive Analytics SoftWare, Versions 18 and 20, Chicago, IL, USA). The crude
incidence of BP was calculated by dividing the number of new BP cases in one year
by the number of individuals who were at risk (the mean number of the 40-year-
old or above NOHD population within each year). The result was given as the
number of BP cases per 1 million persons. The age-adjusted incidences were
calculated by the direct standardization method using the general NOHD
population and the general European population as references. Incidence rate ratios
46
(IRR) of BP were estimated by the Poisson regression model, and the results were
shown as adjusted and unadjusted IRRs. In adjusted IRRs, age at BP diagnosis
(recorded in categories 0–59, 60–69, 70–79, 80–89 and ≥90) and sex were used as
potential confounding factors. The change in incidence over time was analyzed in
the five-year periods 1985–1989, 1990–1994, 1995–1999, 2000–2004, and 2005–
2009. The incidence did not change significantly between the years 1985 and 2004,
thus, these years were combined into one time period (1985–2004), and the mean
incidence level of this combined time period was used as a reference for the later
time period 2005–2009 in the analysis.
When analyzing the mortality of BP patients in different subgroups of
treatment, a Kaplan-Meier survival analysis was applied. Standardized mortality
ratios (SMR) were calculated by an indirect method, and mortality in the BP study
population was compared with mortality in the general population. The impact of
polypharmacy on mortality was calculated in the categories 0, 1–5, 6–10, and 11 or
more drugs in regular use, and hazard ratios (HR) for different categories were
computed by Cox regression analysis. The results were adjusted for age at the time
of the diagnosis and for sex. A negative binomial model was used to calculate the
risk ratio for the categories of numbers of concomitant medications, and statistical
significance was tested by the log-rank test for equality of survival functions. Data
on the age structure and mortality in the general Finnish population were provided
by Statistics Finland (http://www.tilastokeskus.fi), and data on the general
European population by Eurostat (http://epp.eurostat.ec.europa.eu/portal/page/
portal/statistics/search_database).
In the study that investigated the association between BP and neurological and
psychiatric disorders, the association between a preceding neurological or
psychiatric disorder and BP was analyzed using a logistic regression model, and
results were presented as odds ratios (OR). When calculating an association
between BP and a subsequent neurological or psychiatric disorder, Cox regression
analysis was applied, and results were given as hazard ratios (HR). Both of these
statistical models were adjusted for age at the time of the diagnosis and for sex. A
latency period was defined as the period between the date of diagnosis of the BP or
BCC diagnosis to the date of diagnosis of the neurologic or psychiatric disorder of
interest. If the diagnosis of a specified neurological or psychiatric disorder did not
emerge, the follow-up stopped at the date of death or at the date of the last recorded
visit. In the national population, the age-standardized incidence was calculated
using an indirect method.
47
In all three publications, characteristics of the study populations were
expressed as proportions, means, (with standard deviation [SD]) and medians,
when appropriate. All rates and ratios were given with a 95% confidence interval
(95% CI). A two sided P-values less than 0.05 was considered to be statistically
significant.
4.4 Permissions and ethical aspects (I, II, III)
Since this was a register based study, and patients were not contacted, a statement
of the ethical committee was not required. The permission to use data from the
patient records of the Oulu University Hospital was obtained from the Medical
Director of the Oulu University Hospital, and permission to use the national data
was granted by the National Institute of Health and Welfare. A description of the
scientific research data file concerning e.g. data privacy protection was provided to
the Office of the Data Protection Ombudsman, Finland (www.tietosuoja.fi), as
requested.
48
49
5 Results
5.1 Characteristics of the study populations
5.1.1 Characteristics of the Northern Ostrobothnia Hospital District
study population (I, II)
The initial query of the Oulu University Hospital patient records database returned
172 cases of BP living in the NOHD area. Thirteen records were excluded for not
meeting the specified diagnostic criteria and the remaining 159 cases were included
in the final analysis of publication I. There were 80 females and 79 males, the
female-male ratio being almost 1:1, and the mean age at the time of the diagnosis
was 77.0 for females and 76.5 years for males. The youngest BP patient was 40
years old and the oldest was 93. The mean age at diagnosis was 73.4 years between
1985 and 1989, 74.0 between 1990 and 1999, and 79.0 between 2000 and 2009.
The total population living in the NOHD area increased from circa 340 000 to
400 000 between 1985 and 2009, and the proportion of elderly (70–90-year old)
persons increased from 6.6% to 10.0%.
In publication II, the study population of BP patients living in the NOHD area
included 198 patients. The cases diagnosed between 1985 and 2009 were the same
159 patients as in article I. In article II, the study period was extended to include
the years 2010–2013, and 39 additional patients were included. In this study
population, there were 102 females (51.5%) and 96 males (48.5%), the mean±SD
age was 77.5 years ±10.4, and range 40–96 years.
5.1.2 Characteristics of the national study population (III)
The national study population included 4524 BP patients diagnosed in Finnish
Hospitals between 1987 and 2013. The control population consisted of 66138 BCC
patients. All were aged over 40 years. There were 2719 (60.1%) women in the BP
population, and 36240 (54.8%) women in the control population. The mean±SD
age at the time of diagnosis was 77±11 years for BP and 73±12 years for BCC.
50
5.2 Clinical features of bullous pemphigoid (I)
Clinical features were analyzed among the NOHD population according to
information supplied by the patient records of the Oulu University Hospital. In
148/159 (93.1%) of cases BP manifested as typical blisters or erosion of the skin,
and in 11/159 (6.9%) both the skin and oral mucous membranes were affected.
There was no apparent difference between females and males regarding the affected
sites. Diagnosis was made within one month of initial symptom onset in 27.0% of
patients; 72.3% were diagnosed within six months and in 7.6% diagnosis was made
more than 12 months after the initial symptoms were reported. The data on the
onset of symptoms were missing in 5.0% of cases.
5.3 Incidence of bullous pemphigoid (I, III)
In the NOHD area, the crude incidence was 17 new BP cases per 1 million person-
years (95% CI 15 to 20) between 1985 and 2009. When the European standard
population was used as a reference, the age-standardized incidence was 14 BP cases
per 1 million person-years (95% CI 12 to 17). The crude incidence rates in the
periods 1985–1989, 1990–1994, 1995–1999, 2000–2004, and 2005–2009 were 15,
12, 16, 16, and 27, respectively. The incidence of BP was 1.8-fold (IRR=1.8, 95%
CI 1.3 to 2.6, p<0.001) higher in the 2005–2009 period than the mean incidence
level in the 1985–2004 period. The age- and sex-adjusted IRR was 1.4 (95% CI 1.0
to 2.0, p=0.043).
The age-adjusted incidence was 24 (95% CI 19 to 30) for males and 14 (95%
CI 11 to 17) for females. The incidence of BP increased with age in both genders
and was highest among elderly men: 451 new cases per 1 million person-years
among men between 80–89 years, and 1068 new cases per 1 million person-years
among 90–100 -year old men.
In the national BP data, the crude incidence of BP was 25 per 1 million per year
between 1987 and 2013. Using the European standard population as a reference,
the age-adjusted incidence was 18 per 1 million per year. The increasing trend in
the incidence of BP over time was also seen in national population (data not shown),
but it is partly explained by the involvement of outpatient visits from 1998 onwards.
51
5.4 Mortality of bullous pemphigoid (II)
In the study population of 198 BP patients from the NOHD, 33 (16.7%) died within
the first year of diagnosis, and 60 (30.3%) within two years. When 1-year mortality
was compared with that of the age-matched general population, BP patients had
7.6-fold greater risk of death (SMR=7.56, 95% CI 4.98 to 10.14).
5.4.1 Comorbidities and mortality
In the NOHD population (n=198), we found the following comorbidities prior to
the diagnosis of BP: cardiovascular diseases in 76.3% of patients,
neurodegenerative diseases in 40.9%, other skin conditions (non-melanoma skin
cancers included) in 37.4%, type 2 diabetes in 23.2%, malignant disease (excluding
non-melanoma skin cancers) in 8.6% and autoimmune diseases other than BP in
3.5%. Of these, only malignant disease predicted increased 1-year mortality, the
age- and sex-adjusted HR being 2.4 (95% CI 1.1 to 5.5, p=0.047).
5.4.2 Concomitant medications and mortality
Polypharmacy was common among BP patients (n=197): the number of regularly
used concomitant medications (excluding medications for BP) ranged from 0 to 19.
While 14 patients (7.1%) did not have any medication, 85 (43.1%) had 1–5 drugs,
74 (37.6%) 6–10 drugs, and 24 (12.2%) 11 or more drugs.
Polypharmacy had a statistically significant association with mortality, and the
higher the number of drugs was, the greater the 1-year and 2-year mortality. For
example, the patients who had 11 or more drugs in regular use had a 2-fold higher
risk of death within two years than those who had 1–5 drugs (age- and sex-adjusted
HR=2.15, 95% CI 0.99 to 4.67). The number of regularly used drugs increased over
time, since the mean (median) number of drugs was 4.6 (4), 5.1 (5), 6.3 (6) and 7.4
(7) in 1985–1989, 1990–1999, 2000–2009 and 2010–2012, respectively, and a
linear 1.17-fold (95% CI 1.07 to 1.31) increasing trend was seen between time
periods.
5.4.3 Treatment for bullous pemphigoid and mortality
In 124/198 (62.6%) of cases, the first-line treatment for BP in the Oulu University
Hospital was oral prednisolone together with topical corticosteroids (usually 0.1%
52
betamethasone). The second most common first-line treatment was topical
corticosteroid alone in 59/198 (29.8%) of cases, usually for patients with milder
symptoms. Tetracycline (with topical corticosteroids) was the initial treatment in
15/198 (7.6%) of cases. In half of the cases (100/198; 50.5%) only prednisolone
and topical corticosteroids were used, whereas azathioprine was added to
prednisolone in 25 patients, and methotrexate in two patients. Adjuvant therapy has
become more common in recent years, since of those patients treated with
azathioprine 12%, 16%, 28% and 44% were diagnosed in the 1980s, 1990s, 2000s
and 2010s, respectively.
The mortality of BP patients was analyzed according to three different
treatment groups (see Materials and methods: Groupings used in the Northern
Ostrobothnia Hospital District study population). There were 100 patients in group
1 (prednisolone alone), 40 patients in group 2 (topical corticosteroid with or without
tetracycline), and 26 patients in group 3 (prednisolone together with an adjuvant
immunosuppressant). The mean age at diagnosis was 77.8 years in group 1, 82.0 in
group 2, and 72.5 in group 3.
The patients in group 1 seemed to have the lowest 1- and 2-year survival, but
because of limited numbers of cases, especially in group 3, statistical comparison
was not reliable. There were no statistically significant differences between groups
1 and 3 in the mean starting dose of prednisolone (45.6 mg and 46.5 mg in groups
1 and 3, respectively, p=0.79) or in the number of concomitant drugs (6.1, 6.3 and
5.0 in groups 1, 2 and 3, respectively, p=0.41). The mortality rate of the entire
population remained unchanged throughout the study period.
5.5 Association with neurological diseases (III)
Based on the national data, the most prevalent neurological diseases among BP
patients (n=4524) were cerebral infarction (n=859), ‘other or unspecified dementia’
(n=607), and Alzheimer’s disease (n=617). The strongest association was found
between MS and BP: MS patients had 5.9-fold greater risk of incident BP compared
with controls. Dementias were also significantly associated with subsequent BP
with 3.8-fold greater risk in ‘other or unspecified dementia’, 3.6-fold greater risk
in vascular dementia, and 2.6-fold greater risk in Alzheimer’s disease. Several other
central nervous system diseases preceded BP as well: subarachnoid hemorrhage,
intracerebral hemorrhage, and cerebral infarction with 2.1-fold, 2.6-fold, and 1.8-
fold greater risks, respectively, compared with controls. The mean time between
53
dementia and BP was three years whereas MS developed approximately 12 years
before BP.
The analysis of risk for BP patients to develop neurological diseases later in
life, showed a greater risk with e.g. epilepsy (2.0-fold), dementias (1.2–1.8 -fold),
viral meningitis (2.3-fold) and viral encephalitis (2.0-fold).
5.6 Association with psychiatric diseases (III)
The most common (primary) psychiatric diagnoses in patients with BP were
depression (n=259), ‘neurotic, stress-related and somatoform disorders’ (n=132),
and schizotypal and delusional disorders (including schizoaffective disorders)
(n=114). The risk for BP was especially heightened in schizophrenia (2.7-fold), in
schizotypal and delusional disorders (2.1-fold) as well as in personality disorders
(2.2-fold). These disorders preceded BP by approximately 7 to 11 years. In
schizotypal and delusional disorders the risk was bidirectional, and the risk for
these disorders was 1.8-fold in BP patients compared with BCC controls.
54
55
6 Discussion
6.1 Increasing incidence of bullous pemphigoid in Finland (I, III)
This study (I) was among the first to report an increasing incidence of
immunologically confirmed BP in an age- and sex-adjusted study population, and
the first to report the incidence of BP in Nordic countries. The present study showed,
that the incidence of BP in the NOHD increased 1.4-fold between 2005 and 2009
compared with the preceding 20 years. The same kind of increasing trend with the
greatest rise in the 2000s was seen in the national Finnish data (III). The increase
in the incidence of BP in publication I was, however, smaller than that found in
previous studies. A five-fold increase over 11 years has previously been reported in
the UK (Langan et al. 2008), and a three-fold increase over 15 years in France (Joly et al. 2012).
It has been discussed whether improvements in the diagnostics and awareness
of BP could explain the increase in BP incidence (Bertram et al. 2009, Naldi et al. 2012). In publication I, BP diagnoses were verified by direct or indirect IF, which
had been in use over the entire study period. BP180 NC16A ELISA examinations
have been taken in the Oulu University Hospital since 2002, but in the present study,
BP patients diagnosed based only on clinical features and positive ELISA were
excluded from analyses. Moreover, the incidence of BP increased most notably
towards the end of the 2000s, by which time the awareness of BP was widespread
in the primary health care setting in the area from which this study population was
drawn. The Oulu University Hospital has the only dermatology department in the
NOHD area, and the only pathology department capable of performing IF
examinations. Therefore, all suspected BP patients in the area are referred to the
Oulu University Hospital.
The overall incidence of BP in Northern Finland in the 2000s was between 16
and 27 new cases per 1 million person-years. In the 1980s and 1990s, the incidence
varied between 12 and 16 per 1 million person-years. These numbers are close to
the incidences reported in France between 2000 and 2005 (21.7 per 1 million
person-years) (Joly et al. 2012), and in Scotland between 1991 and 2001 (14 per 1
million person-years) (Gudi et al. 2005). Lower incidences were reported in
Germany in the 1980s and 1990s: 6.6 and 6.1 new cases per 1 million person-years
(Jung et al. 1999, Zillikens et al. 1995), and in France during the same era:
approximately 7 BP cases per 1 million person-years (Bernard et al. 1995).
56
The mean age of BP patients in this study did not differ greatly from that found
by previous studies, with the exception of the study by Bernard and his coworkers,
in which the mean age, at 82.4 years, was notably higher (Bernard et al. 1995).
Generally speaking, the Finnish population is somewhat older than the general
European population; the crude incidence over the entire study period in our study
was 17 BP cases per 1 million person-years, and the age-standardized incidence
(using the standard European population as a reference) 14.
When looking at the incidence of BP in Southern Europe and around the
Mediterranean, much lower numbers are seen. The incidences of BP in Tunisia,
Kuwait, and Romania have been reported as 3.84, 2.6, and 2.5 per 1 million person-
years, respectively (Baican et al. 2010, Nanda et al. 2004, Zaraa et al. 2011). In all
of these countries, the reported incidence of pemphigus, another autoimmune skin
disease, is higher than that of BP, with genetic factors, different life expectancies,
and possibly environmental factors, likely contributing to the differences (Alpsoy et al. 2015).
6.2 High mortality among bullous pemphigoid patients (II)
In the present study, the 1- and 2-year mortality rates of BP patients were high, at
16.7% and 30.3%, respectively. In recent European studies, reports of the one-year
mortality of BP patients have ranged between 13% in Spain (Gual et al. 2014) and
approximately 40% in France (Joly et al. 2012, Roujeau et al. 1998). Outside
Europe, reported mortality rates include 11–23% in the USA (Brick et al. 2014a,
Colbert et al. 2004, Parker et al. 2008), 13–23% in China (Li et al. 2013, Zhang et al. 2013), 27% in Singapore (Cai et al. 2013), and 19% in Korea (Lee & Kim 2014).
The somewhat higher mortality rates in France compared with other countries
could be explained by the slightly older age of French study populations, and higher
drop-out rates in some of the studies conducted in other countries (Joly et al. 2012).
Though BP patients are elderly people, the SMR of 7.56 reported in this study
indicates that the risk of death within one year of diagnosis in BP patients is 7.6-
fold greater than that of the reference population of the same age. The SMRs
(calculated for all BP age-groups together) have varied from 1.9 in the USA to 7.6
in our study (Brick et al. 2014a). In Finland, the one-year mortality was quite low,
17%, whereas SMR was among highest. The high SMR might reflect the relatively
older structure of the Finnish population compared to the standard European
population.
57
6.3 Factors increasing the mortality rate in bullous pemphigoid (II)
This study showed that factors that increase the 1-year mortality of BP patients
include polypharmacy and comorbid malignancies. The higher the number of drugs
in regular use, the greater the 1- and 2-year mortality. Polypharmacy can indicate
poor general health, which previous studies have shown to increase mortality
among BP patients (Joly et al. 2005a). Polypharmacy itself was independently
associated with increased mortality in a large population of elderly individuals in a
study by Gomez and coworkers (Gomez et al. 2014). In this study, despite
adjustment for various confounding factors such as age, gender, comorbidities and
smoking status, the risk of death remained 1.8-fold higher in persons receiving six
or more drugs daily compared with those who did not use any medication. Another
population-based study from Kuopio, Finland reported that excessive
polypharmacy (≥10 drugs) was associated with 2.2-fold elevated risk of 5-year
mortality in a population aged 80 years and over (Jyrkka et al. 2009). The main
limitation of the Finnish study was that comorbidities were not adjusted for (Jyrkka et al. 2009).
It can be argued that polypharmacy is a cause rather than a marker of a
heightened risk of death. Nevertheless, there are several theoretical possibilities for
the true causality of this association. Because of altered physiology, elderly people
are prone to the side-effects of drugs, and multiple medications can also result in
unexpected drug-drug or drug-disease interactions. Moreover, drugs that affect the
CNS can potentially cause dizziness and cognitive impairment, both of which
increase the risk of accidents (Gomez et al. 2014, Jyrkka et al. 2009).
Previously, an association between BP and malignancies has been suspected
(Chorzelski et al. 1978), but several recent studies have dispelled such a connection
(Cai et al. 2015, Jedlickova et al. 2010, Lindelof et al. 1990, Ong et al. 2014).
However, as might be expected, those BP patients who also had a diagnosis of a
malignant disease had lower 1-year survival in the present study. Although this
study recorded relatively few malignancies – present in approximately 17 (8.6%)
BP patients, we found a statistically significant 2.4-fold greater risk of death in
those patients compared with BP patients with no accompanying malignancy. The
malignancies detected were heterogeneous including for example tumors of the
gastrointestinal tract, prostate cancer, lung cancer, breast cancer, ovarian cancer,
melanoma, lymphoma and leukemia.
58
6.4 Systemic glucocorticoids and mortality (II)
Systemic glucocorticoids have been the mainstay of BP therapy for decades
(Feliciani et al. 2015, Kirtschig et al. 2010, Venning et al. 2012). However, their
use carries a risk for side-effects, particularly among elderly patients. A prospective
study randomized 341 BP patients to receive either oral prednisone (1mg/kg for
extensive disease, 0.5mg/kg for moderate disease), or topical clobetasol propionate
cream 40g/day (for both extensive and moderate BP) (Joly et al. 2002). In this study,
the overall survival in extensive BP was significantly better in those treated with
topical clobetasol propionate compared with those treated with oral prednisone
1mg/kg. However, there was no difference in survival between topical treatment
group and the prednisone 0.5mg/kg group. Disease control in both extensive and
moderate BP was even better with the topical treatment (Joly et al. 2002).
In the present study, three treatment groups with different expected prognoses
were compared, and a trend towards lower survival of the patients treated solely
with oral prednisolone was seen. Unfortunately, the number of cases, especially in
group 3 (treated with oral prednisolone together with an adjuvant
immunosuppressant) was so small (n=26), that statistical procedures were not
reliable.
Nowadays, the international consensus on glucocorticoid treatment of BP is,
that starting doses of more than 0.75mg/kg of prednisolone should usually be
avoided, but in some treatment resistant cases, doses up to 1 mg/kg may be used
(Feliciani et al. 2015, Kirtschig et al. 2010, Venning et al. 2012). In milder disease,
lower doses can be sufficient to achieve remission (Feliciani et al. 2015, Kirtschig et al. 2010, Venning et al. 2012). More prospective, controlled studies are needed
to investigate glucocorticoid sparing adjuvant therapies and other glucocorticoid-
free potential therapies. A well-designed, prospective, randomized study
comparing doxycycline and oral prednisolone is currently ongoing in the UK and
Germany (Chalmers et al. 2015).
It is not currently possible to predict which patients will experience serious
side-effects when starting systemic glucocorticoid therapy for BP. However,
attention should be paid to factors that increase the toxicity of glucocorticoids, like
low serum albumin, simultaneous use of other drugs that impair gastric mucosa,
and comorbidities like diabetes, osteoporosis and heart failure (Jackson et al. 2007).
59
6.5 Increased risk of bullous pemphigoid in patients with
neurological and psychiatric disorders (III)
To be able to investigate neurological and psychiatric comorbidities with adequate
statistical power, the study population of the third publication was obtained from
the national Finnish Care Register. In publication III, both the CNS and the
peripheral nervous system diseases among BP patients were comprehensively
examined with the very interesting discovery that many neurodegenerative diseases
of the CNS, but none of the peripheral nervous system diseases, were associated
with BP. This finding is in line with the hypothesis that BP180, which is expressed
both in the skin and the CNS, could be an autoantigen that BP shares with many
neurodegenerative diseases (Seppänen 2013). In fact, previous studies have
concentrated mainly on the CNS diseases (Brick et al. 2014b, Chen et al. 2011b,
Langan et al. 2011, Taghipour et al. 2010) and the present study was the first that
also examined the peripheral nervous system diseases on a large scale.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects
both the CNS and the peripheral nervous system (Soinila et al. 2006). However, in
a large, national study population of more than 9000 BP patients, a bidirectional
association was found between BP and ALS (Ong et al. 2013). In the present study,
the number of ALS patients was quite small (n=7), which is probably why no
statistically significant association emerged.
Another new insight made in this study was the association of BP with
psychiatric disorders. Previous studies have not established an association between
BP and schizotypal and delusional disorders, personality disorders, or ‘neurotic,
stress-related and somatoform disorders’ (Bastuji-Garin et al. 2011, Chen et al. 2011b, Teixeira et al. 2014), as did the present study. The results are in line with
those of Chen and coworkers, who reported a 2.6-fold heightened risk of
developing BP in patients with schizophrenia (2.7-fold risk in this study), and a 1.8-
fold heightened risk of BP in patients with bipolar or unipolar disorders (1.5-fold
risk for unipolar, and 1.7-fold risk for bipolar disorder in this study) (Chen et al. 2011b).
However, the strongest association we found was between BP and MS. In
patients with pre-existing MS the risk of BP diagnosis was even 5.9-fold greater
than in non-MS patients. Similarly, another large, population-based study of more
than 5000 MS patients found a 6.7-fold heightened risk of developing BP following
an MS diagnosis (Langer-Gould et al. 2010). In the present study, a significantly
increased risk of BP was found after a diagnosis of dementia. In contrast to other
60
studies, the current study also classified dementias into specific diagnostic
categories, and found, that the risk for BP was 2.6-fold greater in Alzheimer’s
disease, 3.6-fold greater in vascular dementia, and 3.8-fold greater in ‘other or
unspecified dementia’ when compared with non-dementia patients. Despite a well-
recognized epidemiological association, and the identification of shared
autoantigens, the exact molecular mechanisms behind the link between BP and
neurodegenerative diseases are still poorly understood.
It is important for clinicians to be mindful of the risk of BP in neurologically
ill patients, whose ability to report symptoms of BP, such as intense pruritus, may
be impaired. In these cases, anxiety or restlessness may be indicators of pruritus.
Pruritus can also disturb sleep, thereby further impairing memory and cognition.
6.5.1 Pathomechanisms behind the epidemiological association
between bullous pemphigoid and neurological disorders
Some studies have investigated the association between neurological diseases and
BP at molecular level (Chen et al. 2011a, Foureur et al. 2006, Kokkonen et al. 2017,
Recke et al. 2016). Interestingly, serum samples of patients with both BP and
various neurological disorders have been shown to recognize both BP180 and
BP230 antigens in human brain extract (Chen et al. 2011a). A few studies have also
shown IgG autoantibodies to BP180 to be present in the sera of patients with
dementia or Parkinson’s disease in the absence of BP (Foureur et al. 2006,
Kokkonen et al. 2017, Messingham et al. 2016).
A French study comprising 69 dementia patients and 69 controls, all aged over
69 years, measured serum BP180 antibody levels in both groups, and found that
the presence of BP180 antibodies was significantly associated with a diagnosis of
dementia (Foureur et al. 2006). None of the 138 patients had clinical signs of BP
(Foureur et al. 2006).
Another recent study investigated patients with Parkinson’s disease (n=24) and
dementia (n=26), both groups without evidence of an autoimmune skin disease
(Messingham et al. 2016). The control group comprised of 23 dermatological
patients without autoimmune or neurological diseases. In this study, only one
patient with unspecified dementia had autoantibodies to the NC16A region of
BP180 detectable by commercial ELISA. Nevertheless, when reactivity to BP180
outside the NC16A domain, was also investigated by immunoblotting, nine out of
24 (37.5%) Parkinson’s patients and six out of 26 (23.1%) dementia patients had
positive results (Messingham et al. 2016). The authors further investigated the
61
ability of BP180 reactive Parkinson’s patients’ sera to recognize tyrosine-
hydroxylase positive dopaminergic neurons in the rat substantia nigra, a brain
structure that degenerates in humans with Parkinson’s disease. Very interestingly,
all tested serum samples (n=4) colocalized with tyrosine-hydroxylase positive
neurons. Moreover, when BP180 was absorbed from the sera, the neurons of the
substantia nigra were no longer recognized (Messingham et al. 2016).
A study performed by our own department (Kokkonen et al. 2017) investigated
a population of well-characterized patients with Alzheimer’s disease (n=115) and
40 neurologically healthy controls. This study reported that 18% of Alzheimer’s
patients versus 3% of controls had IgG autoantibodies against the NC16A domain
of BP180 in their sera, detected by both ELISA and immunoblotting. NC16A
autoantibody levels also inversely correlated with scores on the Mini-Mental State
Examination (MMSE) i.e. the higher the antibody levels, the lower the MMSE
score, and the more severe the cognitive impairment. However, the sera of 18
Alzheimer’s patients who had autoantibodies to NC16A did not show binding to
the skin basement membrane in an indirect immunofluorescence (IIF) examination,
and none of the patients had any of the skin symptoms characteristic of BP
(Kokkonen et al. 2017).
Results of some other studies contradict these findings. A study that searched
for autoantibodies to BP180 and BP230 in patients with multiple sclerosis (MS)
and Parkinson’s disease, found fewer positive results in neurological patients than
in healthy controls (Recke et al. 2016). One possible explanation to this result is
that patients in this study were relatively young, with the mean age of Parkinson
patients being approximately 63 years and that of MS patients only 33 years (Recke et al. 2016). It was not indicated whether the serum samples of this study were, for
example, taken at the time when the neurological disease was diagnosed. This has
relevance, as epidemiological studies have established that at least clinical
symptoms of BP develop several years after a neurological diagnosis (Cordel et al. 2007, Langan et al. 2011, Taghipour et al. 2010).
The current hypothesis proposed by several research groups (Foureur et al. 2006, Kokkonen et al. 2017, Messingham et al. 2016) is, that BP180 is an antigen
that BP shares with several neurological disorders, which most probably explains
the epidemiological association between these diseases. Still, many details remain
unclear, such as the role of BP180 autoantibodies in progression of
neurodegenerative diseases, and what other factors must accompany the presence
of BP180 NC16A autoantibodies to precipitate an outbreak of BP.
62
6.6 Strengths and limitations of the study
The first and second publications (I, II) each included a well-characterized study
population, selected according to strict inclusion criteria, with every BP diagnosis
confirmed by immunological verification. These studies also had the very long, 25-
year study period. A single researcher (A-K.F) examined all patient records and
collected extensive data on clinical symptoms, treatments, and comorbidities.
However, in the second publication (II), which examined the mortality rate in BP,
the small number of deaths prevented firm conclusions from being drawn. Since all
the studies were based on hospital records, they may have missed any mild cases
of BP that were treated in the primary health care setting.
The third publication (III) captured the second largest BP study population in
the world to date (Chen et al. 2011b, Ong et al. 2013) by using national data from
the Finnish Care Register for Health Care over a long study period. The Finnish
registers are unique worldwide, because they cover practically the entire population
of the country and have been maintained for decades. However, in this register-
based study, it was not possible to verify the diagnoses of BP. One more limitation
was that outpatient visits were only recorded from 1998 onwards in the Care
Register.
6.7 Future prospects
New studies are required to clarify the reasons behind the increase of the incidence
of BP, which is not explained solely by the aging population. As the greatest
increase in its incidence happened in the late 2000s, factors with a rapid effect on
the incidence, such as the availability of new drugs, may be involved. For example,
recent studies have proposed an association between DPP-4 inhibitors and BP
(Bene et al. 2016, Garcia et al. 2016, Stavropoulos et al. 2014). Well-designed
epidemiological studies and studies investigating potential molecular mechanisms
in drug-induced pemphigoid are needed. As discussed above, large, prospective
studies of current treatments for BP are required, as are investigations into
alternatives to glucocorticoid therapy, so that elderly BP patients could be treated
effectively, but without the harmful, in worst case fatal side-effects. Future
challenges include that of describing the molecular mechanisms behind the
association between BP and neurological and psychiatric disorders.
63
7 Conclusions
Based on studies I-III, the following conclusions can be drawn:
– The present incidence of BP in Finland is approximately 27 new cases per 1
million persons per year, and the incidence has increased over time.
– Based on the Northern Finland study population, the mortality rate within one
year of a BP diagnosis is approximately 17%, and the SMR is 7.6.
– Common comorbidities in BP patients are: cardiovascular diseases (76%),
neurodegenerative diseases (41%), skin conditions other than BP (37%), and
type 2 diabetes (23%).
– A diagnosis of malignant disease before BP was present in 8.6% of cases, and
a malignant disease predicted a 2.4-fold increased risk of one-year mortality.
– Polypharmacy is common in BP patients, and it is associated with increased
mortality.
– Many diseases of the CNS that cause neurodegeneration or neuroinflammation,
and many psychiatric disorders are associated with BP. The association is
stronger when the neurological or psychiatric disorder precedes BP than vice
versa.
– The strongest association between BP and a neurodegenerative disease is that
with MS.
– Diseases of the peripheral nervous system are not associated with BP.
64
65
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Original publications
I Försti A-K, Jokelainen J, Timonen M & Tasanen K (2014) Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol 171(5): 1223-1226.
II Försti A-K, Jokelainen J, Timonen M & Tasanen K (2016) Risk of Death in Bullous Pemphigoid: A Retrospective Database Study in Finland. Acta Derm Venereol 96(6): 758-761.
III Försti AK, Jokelainen J, Ansakorpi H, Seppänen A, Majamaa K, Timonen M, Tasanen K. (2016) Psychiatric and neurological disorders are associated with bullous pemphigoid - a nationwide Finnish Care Register study. Sci Rep 6:37125, doi: 10.1038/srep37125.
Reprinted with permission from John Wiley and Sons (I), Medicaljournals.se (II),
and Nature Publishing Group (III).
Original publications are not included in the electronic version of the dissertation.
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INCIDENCE, MORTALITY, COMORBIDITIES, AND TREATMENT OF BULLOUS PEMPHIGOID IN FINLAND
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