- Email: [email protected]
Prevalence and Age Distribution of Pemphigus and Pemphigoid Diseases in Germany
Accepted Manuscript Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany Franziska Hübner, Andreas Recke, Detlef Zillikens, Roland Linder, Enno Schmidt PII:
S0022-202X(16)32122-4
DOI:
10.1016/j.jid.2016.07.013
Reference:
JID 459
To appear in:
The Journal of Investigative Dermatology
Received Date: 4 April 2016 Revised Date:
11 July 2016
Accepted Date: 12 July 2016
Please cite this article as: Hübner F, Recke A, Zillikens D, Linder R, Schmidt E, Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany, The Journal of Investigative Dermatology (2016), doi: 10.1016/j.jid.2016.07.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Letter
Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany
RI PT
Franziska Hübner1, Andreas Recke2, Detlef Zillikens¹, Roland Linder3, Enno Schmidt1,2 ¹Department of Dermatology, University of Lübeck, Lübeck, Germany 2
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck,
3
SC
Germany
Scientific Institute of Techniker Krankenkasse for Benefit and Efficiency in Health Care
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(WINEG), Hamburg, Germany
Correspondence to:
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Enno Schmidt, MD, PhD, Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany, Phone: +49-451-500-4698, Fax: +49-451-500-5162,
EP
mail: [email protected]
Total number of words: 1,321
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Total number of figures/tables: 2 Total number of references: 20
1
ACCEPTED MANUSCRIPT Dear Editor, autoimmune bullous diseases (AIBD) are characterised by autoantibodies against structural proteins of the epidermis (pemphigus vulgaris and foliaceus) and dermalepidermal junction (bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA disease, and epidermolysis bullosa acquisita) (Schmidt and Groves,
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2016). Clinically, blisters and erosions arise on skin and surface-close mucous membranes. Several reports have estimated the incidence of all AIBDs between 13.3 and 66 /million/ year in Germany, U.K., Switzerland, France, Finland, Italy, and the U.S. with highest incidences of
SC
bullous pemphigoid in the population of above 80 years of age (150-300 /millions/ year) and lowest for epidermolysis bullous acquisita (0.2-0.5 /millions/year) (Bertram et al., 2009;
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Brick et al., 2014; Cozzani et al., 2001; Forsti et al., 2014; Joly et al., 2012; Langan et al., 2008; Marazza et al., 2009) (reviewed in (Schmidt et al., 2015)). In contrast, data about the prevalence of AIBDs are scarce.
Here, we analysed the data base of a major German health insurance company, the Techniker
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Krankenkasse, which insures about 9.5 million individuals representing about 12% of the German population. Diagnoses were based on the ICD-10-GM 2011 classification and included all living individuals in 2014. To control for a slightly different demographical
EP
composition of the insured individuals regarding age and sex, data were adjusted to the
AC C
general German population based on the data of the Federal Statistical Office of Germany for the year 2014. We have previously applied a similar approach to estimate the association of AIBDs with malignancies (Schulze et al., 2015). The prevalence of pemphigus and pemphigoid diseases (excluding ICD L13.8, other bullous dermatoses, and L13.9, bullous dermatosis, not further specified) in 2014 was calculated to 0.5‰, resulting in a total number of about 40,400 patients in the total population of 80.925 million inhabitants in Germany. Bullous pemphigoid had the highest prevalence of all AIBDs (259.3 patients/ million) followed by pemphigus vulgaris (94.8 patients/ million), mucous membrane pemphigoid (24.6 patients/ million), and chronic bullous dermatosis of childhood 2
ACCEPTED MANUSCRIPT (24.3 patients/ million inhabitants <18 years of age). Lower prevalences were seen for pemphigoid gestationis (13.6/ million females), pemphigus foliaceus (10.0/ million) and epidermolysis bullosa acquisita (2.8/ million) (Table). The prevalences for all analysed ICD codes are shown in the Table.
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In patients with more than one specific ICD code for AIBDs, patients were allocated to the individual ICD codes according to their relative frequency. When patients with more than one ICD code within the group of AIBD diagnoses included the unspecific ICD codes L10.9
SC
(pemphigus, not further specified) and L12.9 (pemphigoid, not further specified), the patient was classified according to the specific code. While the exact diagnosis could not be
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determined in these patients, the total prevalence of AIBDs is not affected. In a previous study from Denmark in 2006 about the prevalence of autoimmune diseases, pemphigus (L10) and pemphigoid diseases (L12) were also included and their prevalences estimated to be 60/ million and 120/million, respectively (Eaton et al., 2010. The higher
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prevalence of pemphigoid diseases in the present study (data from 2014) may be explained in part by the improved diagnostic techniques and the increased incidence of the by far most frequent AIBD, bullous pemphigoid, for which a 2-4-fold increased incidence within the last
EP
decade has been reported in central Europe and the U.K. (Bertram et al., 2009; Joly et al.,
AC C
2012; Langan et al., 2008). The higher prevalence of pemphigus diseases in Germany compared to Denmark may be, at least in part, due to the higher number of inhabitants with Mediterranean origin where the incidence of pemphigus is at least 2-fold higher (Hahn-Ristic et al., 2002).
While the incidence of bullous pemphigoid has been reported to be about 10-15 times higher compared to pemphigus vulgaris/ foliaceus (Bertram et al., 2009; Joly et al., 2012; Langan et al., 2008; Marazza et al., 2009), in the present study, the prevalence of bullous pemphigoid was determined to be only 2.5-fold higher compared to pemphigus. This difference may reflect the much longer disease course in pemphigus patients well known to the clinician and 3
ACCEPTED MANUSCRIPT the old age of patients with bullous pemphigoid. Moreover, the high one-year mortality after the diagnosis of bullous pemphigoid of between 20-40% (Cortes et al., 2011; Joly et al., 2012; Langan et al., 2008; Parker et al., 2008; Rzany et al., 2002) (reviewed in (Schmidt et al., 2015)) may also contribute to the observed difference between the incidence to prevalence
RI PT
ration in bullous pemphigoid and pemphigus. The prevalence of bullous pemphigoid of 259 / million in the present study indicates a disease duration of about 15 years based on the published incidence data of 13.4/ million/ year in a
SC
study from 2001/ 2002 in a single tertiary referral center in Lower Franconia, Germany (Bertram et al., 2009). A 2-4-fold increased incidence within one decade as described from
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Lower Franconia, France, and the U.K. (Bertram et al., 2009; Joly et al., 2012; Langan et al., 2008) may result in an incidence of 30-40/ million/ year in 2014. Based on these data a disease duration of 6-8 years can be calculated for bullous pemphigoid. For the analysis of the age distribution of major AIBDs, only patients with a distinct ICD
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coding were included. In line with previous reports, bullous pemphigoid and mucous membrane pemphigoid were more frequent in the elderly population while pemphigus diseases predominately occurred in the middle age (Schmidt et al., 2015). While it is known
EP
that most of the patients with epidermolysis bullosa acquisita affect the elderly, we saw a
AC C
second peak of disease onset in the first three decades of life (Figure). A limitation of the present study was its dependence of ICD-10 coding of medical personnel of all specialities during both in- and out-patient treatments as discussed previously (Hsu et al., 2015; Schulze et al., 2015). Coding errors may be due to coding personnel that is not familiar with the sophisticated nomenclature of AIBDs or does not appreciate the subtle differences between the different codes and AIBDs, respectively. This assumption is supported by the relatively high number of unspecific coding (L10.9 and L12.9) that accounted for 15% of AIBD diagnoses.
4
ACCEPTED MANUSCRIPT An estimation of the coding quality may be derived from pemphigoid gestationis, an AIBD occurring during pregnancies or the postpartum period (Schmidt and Zillikens, 2013). Pemphigoid gestationis was diagnosed in no males but in 23 women older than 50 years resulting in a false-coding rate of 4.5%. To further evaluate the data quality, three other
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chronic inflammatory dermatoses with known prevalences in Germany were included and were in line with previously reported prevalence data (psoriasis, 2.5%; alopecia areata, 0.2%; vitiligo, 0.5%) (Augustin et al., 2010; Gilhar et al., 2012; Taieb and Picardo, 2009) (Table).
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The lower prevalence of psoriasis in the present study may be explained by the restriction to L40.0 (psoriasis vulgaris) in contrast to the study by Augustin and co-worker that evaluated
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all psoriasis ICDs including L40.9 (Psoriasis, not further specified) (Augustin et al., 2010). Another shortcoming of the present approach is that some relevant AIBDs, i.e. linear IgA disease and anti-p200/ laminin γ1 pemphigoid could not be analysed due to the lack of specific ICD-10 codes. Latter diseases are coded as L12.8 (other pemphigoid disorders).
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When analysing the age distribution of L12.2, chronic bullous dermatosis of childhood, the majority (63%) of patients was older than 18 years with a median age of 47 years. The most likely explanation for this systematic miscoding is the synonymous use of chronic bullous
EP
dermatosis of childhood and linear IgA dermatosis of childhood. This may have led many clinicians to code also adult patients with linear IgA diseases as L.12.2 (instead of L12.8).
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This mistake may have also been fostered by the lack of a specific ICD code for linear IgA disease of adults (see above). We, therefore, speculate that most adult patients encoded with L12.2 suffered from linear IgA disease. In summary, this study provides prevalences and age distributions of pemphigus and pemphigoid diseases based on a large patient collective in Germany.
5
ACCEPTED MANUSCRIPT Acknowledgement
All authors declare no conflict of interest. This study received structural support by Deutsche
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Forschungsgemeinschaft EXC 306/2 Inflammation at Interfaces.
Conflict of Interest
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The authors state no conflict of interest.
6
ACCEPTED MANUSCRIPT References Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm Venereol 2010;90:147-51.
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Bertram F, Brocker EB, Zillikens D, Schmidt E. Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges 2009;7:434-40.
SC
Brick KE, Weaver CH, Lohse CM, Pittelkow MR, Lehman JS, Camilleri MJ, et al. Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009. J Am Acad Dermatol 2014;71:92-9.
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Cortes B, Marazza G, Naldi L, Combescure C, Borradori L. Mortality of bullous pemphigoid in Switzerland: a prospective study. Br J Dermatol 2011;165:368-74. Cozzani E, Parodi A, Rebora A, Delmonte S, Barile M, Nigro A, et al. Bullous pemphigoid in Liguria: a 2-year survey. J Eur Acad Dermatol Venereol 2001;15:317-9.
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Eaton WW, Pedersen MG, Atladottir HO, Gregory PE, Rose NR, Mortensen PB. The prevalence of 30 ICD-10 autoimmune diseases in Denmark. Immunol Res 2010;47:228-31. Forsti AK, Jokelainen J, Timonen M, Tasanen K. Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol 2014;171:1223-6.
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Gilhar A, Etzioni A, Paus R. Alopecia areata. N Engl J Med 2012;366:1515-25.
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Hahn-Ristic K, Rzany B, Amagai M, Brocker EB, Zillikens D. Increased incidence of pemphigus vulgaris in southern Europeans living in Germany compared with native Germans. J Eur Acad Dermatol Venereol 2002;16:68-71. Hsu D, Brieva J, Nardone B, Silverberg JI. Validation of database search strategies for the epidemiological study of pemphigus and pemphigoid. Br J Dermatol 2016;174:645-8. Joly P, Baricault S, Sparsa A, Bernard P, Bedane C, Duvert-Lehembre S, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012;132:1998-2004. Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and pemphigus vulgaris - incidence and mortality in the UK: population based cohort study. BMJ 2008;337:a180. 7
ACCEPTED MANUSCRIPT Marazza G, Pham HC, Scharer L, Pedrazzetti PP, Hunziker T, Trueb RM, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol 2009;161:861-8.
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Parker SR, Dyson S, Brisman S, Pennie M, Swerlick RA, Khan R, et al. Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008;59:582-8.
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Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B, et al. Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 2002;138:903-8.
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Schmidt E, Borradori L, Joly P. Epidemiology of autoimmune bullous diseases. In: Murrell D (Eds) Blistering diseases. Heidelberg, Germany: Springer; 2015. 1st edition, p. 251-64. Schmidt E, Groves R. Immunobullous diseases. In: Griffith C, Barker J, Chalmers, Bleiker T, Creamer D (Eds) Rook's Textbook of Dermatology. Chichester, UK: Wiley-Blackwell: 2016 9th edition, part 3, chapter 50. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013; 381:320-32.
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Schulze F, Neumann K, Recke A, Zillikens D, Linder R, Schmidt E. Malignancies in pemphigus and pemphigoid diseases. J Invest Dermatol 2015;135:1445-7.
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Taieb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med 2009;360:160-9.
8
ACCEPTED MANUSCRIPT Table. Prevalences of autoimmune blistering diseases and other chronic inflammatory dermatoses in Germany in 2014* Diseases
ICD-10
Patient numbers1
Prevalence in males2
Prevalence Prevalence in females2 total2
Pemphigoid diseases Mucous membrane pemphigoid
L12.1
L12.2 Chronic bullous dermatosis of childhood <18 years ≥ 18 years
21,055
226.54
1,994 857
18.37 7.12
318 539
22.03 4.02
290.86
259.30
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L12.0
30.52 13.9
24.56 10.34
26.72 11.58
24.27 7.90
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Bullous pemphigoid
O26.4
563
0.00
13.61
6.93
Epidermolysis bullosa acquisita
L12.3
230
2.71
2.97
2.84
Other pemphigoid disorders3
L12.8
385
3.99
5.47
4.74
Pemphigoid disorders, not further specified
L12.9
3,200
35.56
43.12
39.41
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Pemphigoid gestationis
Pemphigus diseases Pemphigus vegetans Pemphigus foliaceus
7,699
81.05
108.08
94.82
L10.1
318
4.40
3.45
3.91
L10.2
813
9.04
10.94
10.01
L10.8
391
3.55
6.03
4.82
2,925
33.49
38.47
36.03
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Other pemphigus disorders
L10.0
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Pemphigus vulgaris
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Pemphigus diseases, not further specified
L10.9
Other inflammatory dermatoses
Psoriasis vulgaris
L40.0
1,000,29
12,841
11,342.51
12,319.25
Alopecia areata
L63
171,890
2,565.4
1,590.4
2,116.9
L80 168,848 2,066.81 2,015.4 2,079.5 Vitiligo * calculated for 9.457.303 consistent insured persons in 2014 1 adjusted to the general German population based on the data of the Federal Statistical Office of Germany in 2014 2 per million insured persons 3 including linear IgA disease and anti-p200/ laminin γ1 pemphigoid
9
ACCEPTED MANUSCRIPT Figure legends
Figure. Age distribution of selected autoimmune blistering diseases in Germany. Age distribution per decade for pemphigoid (upper panel) and pemphigus disorders (middle panel)
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based on ICD-10 2011 codes of a major health insurance company analysed for 2014. Combined violin and box plots of age distributions (lower panel) with violin width representing the prevalence compared to the age-matched general German population, and
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box plots showing the median and quartiles of patient age. For L12.2 (chronic bullous dermatosis of childhood), box plots are shown for patients < 18 and ≥ 18 years of age. Coding
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of adults patients as L12.2 is discussed in the text.
10
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EP
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SC
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ACCEPTED MANUSCRIPT
S0022-202X(16)32122-4
DOI:
10.1016/j.jid.2016.07.013
Reference:
JID 459
To appear in:
The Journal of Investigative Dermatology
Received Date: 4 April 2016 Revised Date:
11 July 2016
Accepted Date: 12 July 2016
Please cite this article as: Hübner F, Recke A, Zillikens D, Linder R, Schmidt E, Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany, The Journal of Investigative Dermatology (2016), doi: 10.1016/j.jid.2016.07.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Letter
Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany
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Franziska Hübner1, Andreas Recke2, Detlef Zillikens¹, Roland Linder3, Enno Schmidt1,2 ¹Department of Dermatology, University of Lübeck, Lübeck, Germany 2
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck,
3
SC
Germany
Scientific Institute of Techniker Krankenkasse for Benefit and Efficiency in Health Care
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(WINEG), Hamburg, Germany
Correspondence to:
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Enno Schmidt, MD, PhD, Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany, Phone: +49-451-500-4698, Fax: +49-451-500-5162,
EP
mail: [email protected]
Total number of words: 1,321
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Total number of figures/tables: 2 Total number of references: 20
1
ACCEPTED MANUSCRIPT Dear Editor, autoimmune bullous diseases (AIBD) are characterised by autoantibodies against structural proteins of the epidermis (pemphigus vulgaris and foliaceus) and dermalepidermal junction (bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA disease, and epidermolysis bullosa acquisita) (Schmidt and Groves,
RI PT
2016). Clinically, blisters and erosions arise on skin and surface-close mucous membranes. Several reports have estimated the incidence of all AIBDs between 13.3 and 66 /million/ year in Germany, U.K., Switzerland, France, Finland, Italy, and the U.S. with highest incidences of
SC
bullous pemphigoid in the population of above 80 years of age (150-300 /millions/ year) and lowest for epidermolysis bullous acquisita (0.2-0.5 /millions/year) (Bertram et al., 2009;
M AN U
Brick et al., 2014; Cozzani et al., 2001; Forsti et al., 2014; Joly et al., 2012; Langan et al., 2008; Marazza et al., 2009) (reviewed in (Schmidt et al., 2015)). In contrast, data about the prevalence of AIBDs are scarce.
Here, we analysed the data base of a major German health insurance company, the Techniker
TE D
Krankenkasse, which insures about 9.5 million individuals representing about 12% of the German population. Diagnoses were based on the ICD-10-GM 2011 classification and included all living individuals in 2014. To control for a slightly different demographical
EP
composition of the insured individuals regarding age and sex, data were adjusted to the
AC C
general German population based on the data of the Federal Statistical Office of Germany for the year 2014. We have previously applied a similar approach to estimate the association of AIBDs with malignancies (Schulze et al., 2015). The prevalence of pemphigus and pemphigoid diseases (excluding ICD L13.8, other bullous dermatoses, and L13.9, bullous dermatosis, not further specified) in 2014 was calculated to 0.5‰, resulting in a total number of about 40,400 patients in the total population of 80.925 million inhabitants in Germany. Bullous pemphigoid had the highest prevalence of all AIBDs (259.3 patients/ million) followed by pemphigus vulgaris (94.8 patients/ million), mucous membrane pemphigoid (24.6 patients/ million), and chronic bullous dermatosis of childhood 2
ACCEPTED MANUSCRIPT (24.3 patients/ million inhabitants <18 years of age). Lower prevalences were seen for pemphigoid gestationis (13.6/ million females), pemphigus foliaceus (10.0/ million) and epidermolysis bullosa acquisita (2.8/ million) (Table). The prevalences for all analysed ICD codes are shown in the Table.
RI PT
In patients with more than one specific ICD code for AIBDs, patients were allocated to the individual ICD codes according to their relative frequency. When patients with more than one ICD code within the group of AIBD diagnoses included the unspecific ICD codes L10.9
SC
(pemphigus, not further specified) and L12.9 (pemphigoid, not further specified), the patient was classified according to the specific code. While the exact diagnosis could not be
M AN U
determined in these patients, the total prevalence of AIBDs is not affected. In a previous study from Denmark in 2006 about the prevalence of autoimmune diseases, pemphigus (L10) and pemphigoid diseases (L12) were also included and their prevalences estimated to be 60/ million and 120/million, respectively (Eaton et al., 2010. The higher
TE D
prevalence of pemphigoid diseases in the present study (data from 2014) may be explained in part by the improved diagnostic techniques and the increased incidence of the by far most frequent AIBD, bullous pemphigoid, for which a 2-4-fold increased incidence within the last
EP
decade has been reported in central Europe and the U.K. (Bertram et al., 2009; Joly et al.,
AC C
2012; Langan et al., 2008). The higher prevalence of pemphigus diseases in Germany compared to Denmark may be, at least in part, due to the higher number of inhabitants with Mediterranean origin where the incidence of pemphigus is at least 2-fold higher (Hahn-Ristic et al., 2002).
While the incidence of bullous pemphigoid has been reported to be about 10-15 times higher compared to pemphigus vulgaris/ foliaceus (Bertram et al., 2009; Joly et al., 2012; Langan et al., 2008; Marazza et al., 2009), in the present study, the prevalence of bullous pemphigoid was determined to be only 2.5-fold higher compared to pemphigus. This difference may reflect the much longer disease course in pemphigus patients well known to the clinician and 3
ACCEPTED MANUSCRIPT the old age of patients with bullous pemphigoid. Moreover, the high one-year mortality after the diagnosis of bullous pemphigoid of between 20-40% (Cortes et al., 2011; Joly et al., 2012; Langan et al., 2008; Parker et al., 2008; Rzany et al., 2002) (reviewed in (Schmidt et al., 2015)) may also contribute to the observed difference between the incidence to prevalence
RI PT
ration in bullous pemphigoid and pemphigus. The prevalence of bullous pemphigoid of 259 / million in the present study indicates a disease duration of about 15 years based on the published incidence data of 13.4/ million/ year in a
SC
study from 2001/ 2002 in a single tertiary referral center in Lower Franconia, Germany (Bertram et al., 2009). A 2-4-fold increased incidence within one decade as described from
M AN U
Lower Franconia, France, and the U.K. (Bertram et al., 2009; Joly et al., 2012; Langan et al., 2008) may result in an incidence of 30-40/ million/ year in 2014. Based on these data a disease duration of 6-8 years can be calculated for bullous pemphigoid. For the analysis of the age distribution of major AIBDs, only patients with a distinct ICD
TE D
coding were included. In line with previous reports, bullous pemphigoid and mucous membrane pemphigoid were more frequent in the elderly population while pemphigus diseases predominately occurred in the middle age (Schmidt et al., 2015). While it is known
EP
that most of the patients with epidermolysis bullosa acquisita affect the elderly, we saw a
AC C
second peak of disease onset in the first three decades of life (Figure). A limitation of the present study was its dependence of ICD-10 coding of medical personnel of all specialities during both in- and out-patient treatments as discussed previously (Hsu et al., 2015; Schulze et al., 2015). Coding errors may be due to coding personnel that is not familiar with the sophisticated nomenclature of AIBDs or does not appreciate the subtle differences between the different codes and AIBDs, respectively. This assumption is supported by the relatively high number of unspecific coding (L10.9 and L12.9) that accounted for 15% of AIBD diagnoses.
4
ACCEPTED MANUSCRIPT An estimation of the coding quality may be derived from pemphigoid gestationis, an AIBD occurring during pregnancies or the postpartum period (Schmidt and Zillikens, 2013). Pemphigoid gestationis was diagnosed in no males but in 23 women older than 50 years resulting in a false-coding rate of 4.5%. To further evaluate the data quality, three other
RI PT
chronic inflammatory dermatoses with known prevalences in Germany were included and were in line with previously reported prevalence data (psoriasis, 2.5%; alopecia areata, 0.2%; vitiligo, 0.5%) (Augustin et al., 2010; Gilhar et al., 2012; Taieb and Picardo, 2009) (Table).
SC
The lower prevalence of psoriasis in the present study may be explained by the restriction to L40.0 (psoriasis vulgaris) in contrast to the study by Augustin and co-worker that evaluated
M AN U
all psoriasis ICDs including L40.9 (Psoriasis, not further specified) (Augustin et al., 2010). Another shortcoming of the present approach is that some relevant AIBDs, i.e. linear IgA disease and anti-p200/ laminin γ1 pemphigoid could not be analysed due to the lack of specific ICD-10 codes. Latter diseases are coded as L12.8 (other pemphigoid disorders).
TE D
When analysing the age distribution of L12.2, chronic bullous dermatosis of childhood, the majority (63%) of patients was older than 18 years with a median age of 47 years. The most likely explanation for this systematic miscoding is the synonymous use of chronic bullous
EP
dermatosis of childhood and linear IgA dermatosis of childhood. This may have led many clinicians to code also adult patients with linear IgA diseases as L.12.2 (instead of L12.8).
AC C
This mistake may have also been fostered by the lack of a specific ICD code for linear IgA disease of adults (see above). We, therefore, speculate that most adult patients encoded with L12.2 suffered from linear IgA disease. In summary, this study provides prevalences and age distributions of pemphigus and pemphigoid diseases based on a large patient collective in Germany.
5
ACCEPTED MANUSCRIPT Acknowledgement
All authors declare no conflict of interest. This study received structural support by Deutsche
RI PT
Forschungsgemeinschaft EXC 306/2 Inflammation at Interfaces.
Conflict of Interest
AC C
EP
TE D
M AN U
SC
The authors state no conflict of interest.
6
ACCEPTED MANUSCRIPT References Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm Venereol 2010;90:147-51.
RI PT
Bertram F, Brocker EB, Zillikens D, Schmidt E. Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges 2009;7:434-40.
SC
Brick KE, Weaver CH, Lohse CM, Pittelkow MR, Lehman JS, Camilleri MJ, et al. Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009. J Am Acad Dermatol 2014;71:92-9.
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Cortes B, Marazza G, Naldi L, Combescure C, Borradori L. Mortality of bullous pemphigoid in Switzerland: a prospective study. Br J Dermatol 2011;165:368-74. Cozzani E, Parodi A, Rebora A, Delmonte S, Barile M, Nigro A, et al. Bullous pemphigoid in Liguria: a 2-year survey. J Eur Acad Dermatol Venereol 2001;15:317-9.
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Eaton WW, Pedersen MG, Atladottir HO, Gregory PE, Rose NR, Mortensen PB. The prevalence of 30 ICD-10 autoimmune diseases in Denmark. Immunol Res 2010;47:228-31. Forsti AK, Jokelainen J, Timonen M, Tasanen K. Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol 2014;171:1223-6.
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Hahn-Ristic K, Rzany B, Amagai M, Brocker EB, Zillikens D. Increased incidence of pemphigus vulgaris in southern Europeans living in Germany compared with native Germans. J Eur Acad Dermatol Venereol 2002;16:68-71. Hsu D, Brieva J, Nardone B, Silverberg JI. Validation of database search strategies for the epidemiological study of pemphigus and pemphigoid. Br J Dermatol 2016;174:645-8. Joly P, Baricault S, Sparsa A, Bernard P, Bedane C, Duvert-Lehembre S, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012;132:1998-2004. Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and pemphigus vulgaris - incidence and mortality in the UK: population based cohort study. BMJ 2008;337:a180. 7
ACCEPTED MANUSCRIPT Marazza G, Pham HC, Scharer L, Pedrazzetti PP, Hunziker T, Trueb RM, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol 2009;161:861-8.
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ACCEPTED MANUSCRIPT Table. Prevalences of autoimmune blistering diseases and other chronic inflammatory dermatoses in Germany in 2014* Diseases
ICD-10
Patient numbers1
Prevalence in males2
Prevalence Prevalence in females2 total2
Pemphigoid diseases Mucous membrane pemphigoid
L12.1
L12.2 Chronic bullous dermatosis of childhood <18 years ≥ 18 years
21,055
226.54
1,994 857
18.37 7.12
318 539
22.03 4.02
290.86
259.30
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L12.0
30.52 13.9
24.56 10.34
26.72 11.58
24.27 7.90
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Bullous pemphigoid
O26.4
563
0.00
13.61
6.93
Epidermolysis bullosa acquisita
L12.3
230
2.71
2.97
2.84
Other pemphigoid disorders3
L12.8
385
3.99
5.47
4.74
Pemphigoid disorders, not further specified
L12.9
3,200
35.56
43.12
39.41
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Pemphigoid gestationis
Pemphigus diseases Pemphigus vegetans Pemphigus foliaceus
7,699
81.05
108.08
94.82
L10.1
318
4.40
3.45
3.91
L10.2
813
9.04
10.94
10.01
L10.8
391
3.55
6.03
4.82
2,925
33.49
38.47
36.03
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Other pemphigus disorders
L10.0
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Pemphigus vulgaris
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Pemphigus diseases, not further specified
L10.9
Other inflammatory dermatoses
Psoriasis vulgaris
L40.0
1,000,29
12,841
11,342.51
12,319.25
Alopecia areata
L63
171,890
2,565.4
1,590.4
2,116.9
L80 168,848 2,066.81 2,015.4 2,079.5 Vitiligo * calculated for 9.457.303 consistent insured persons in 2014 1 adjusted to the general German population based on the data of the Federal Statistical Office of Germany in 2014 2 per million insured persons 3 including linear IgA disease and anti-p200/ laminin γ1 pemphigoid
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ACCEPTED MANUSCRIPT Figure legends
Figure. Age distribution of selected autoimmune blistering diseases in Germany. Age distribution per decade for pemphigoid (upper panel) and pemphigus disorders (middle panel)
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based on ICD-10 2011 codes of a major health insurance company analysed for 2014. Combined violin and box plots of age distributions (lower panel) with violin width representing the prevalence compared to the age-matched general German population, and
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box plots showing the median and quartiles of patient age. For L12.2 (chronic bullous dermatosis of childhood), box plots are shown for patients < 18 and ≥ 18 years of age. Coding
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of adults patients as L12.2 is discussed in the text.
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