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      Psychiatric and neurological disorders are associated with bullous pemphigoid – a nationwide Finnish Care Register study

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          Abstract

          Bullous pemphigoid (BP) is an autoimmune blistering skin disease with increasing incidence. BP is associated with neurological disorders, but it has not been established, what subtypes of dementia and stroke are associated with BP, and what is the temporal relation between these diseases. Also, the association between BP and psychiatric disorders is controversial. We conducted a retrospective nationwide study, using the Finnish Care Register for Health Care diagnoses between 1987 and 2013. The study population of 4524 BP patients were compared with 66138 patients with basocellular carcinoma (BCC), neurological and psychiatric comorbid disorders were evaluated for both groups, and associations were estimated by Cox regression and logistic regression analyses. The strongest risk of developing BP was found after diagnosis of multiple sclerosis (MS) (OR=5.9, 95% CI 3.9–8.5). Among psychiatric diseases, the corresponding risk was strongest in schizophrenia (OR=2.7, 95% CI 2.0–3.5), and as a novel finding, also personality disorders (OR=2.2, 95% CI 1.3–3.3) preceded BP. In conclusion, many psychiatric disorders, especially schizophrenia, carry heightened risk for BP. Furthermore, several neurological diseases which cause central nervous system inflammation or degeneration were related to BP, and the association was strongest between MS and BP.

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          Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study.

          Bullous pemphigoid (BP), pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune bullous diseases characterized by the presence of tissue-bound and circulating autoantibodies directed against disease-specific target antigens of the skin. Although rare, these diseases run a chronic course and are associated with significant morbidity and mortality. There are few prospective data on gender- and age-specific incidence of these disorders. Our aims were: (i) to evaluate the incidence of BP and PV/PF in Swiss patients, as the primary endpoint; and (ii) to assess the profile of the patients, particularly for comorbidities and medications, as the secondary endpoint. The protocol of the study was distributed to all dermatology clinics, immunopathology laboratories and practising dermatologists in Switzerland. All newly diagnosed cases of BP and pemphigus occurring between 1 January 2001 and 31 December 2002 were collected. In total, 168 patients (73 men and 95 women) with these autoimmune bullous diseases, with a diagnosis based on clinical, histological and immunopathological criteria, were finally included. BP showed a mean incidence of 12.1 new cases per million people per year. Its incidence increased significantly after the age of 70 years, with a maximal value after the age of 90 years. The female/male ratio was 1.3. The age-standardized incidence of BP using the European population as reference was, however, lower, with 6.8 new cases per million people per year, reflecting the ageing of the Swiss population. In contrast, both PV and PF were less frequent. Their combined mean incidence was 0.6 new cases per million people per year. CONCLUSIONS; This is the first comprehensive prospective study analysing the incidence of autoimmune bullous diseases in an entire country. Our patient cohort is large enough to establish BP as the most frequent autoimmune bullous disease. Its incidence rate appears higher compared with other previous studies, most likely because of the demographic characteristics of the Swiss population. Nevertheless, based on its potentially misleading presentations, it is possible that the real incidence rate of BP is still underestimated. Based on its significant incidence in the elderly population, BP should deserve more public health concern.
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            Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid.

            Autoimmune bullous diseases are rare, organ-specific, a group of blistering disease of skin and mucous membranes. Recent studies suggest that the frequency of the autoimmune bullous diseases has been increasing. Pemphigus vulgaris and bullous pemphigoid are the most frequently reported autoimmune bullous diseases. High incidence of autoimmune bullous diseases in some ethnic groups such as pemphigus in Ashkenazi Jewish, or in some regions such as pemphigus foliaceus in Brazil has been shown to be related to genetic and environmental factors, respectively. Pemphigus has been reported more frequently in the female gender. Although it is most frequently diagnosed between the ages 50 and 60 in European countries, in the remaining countries in the world, it is seen between the ages of 30 and 50. Bullous pemphigoid is generally seen above 70 years of age. Although overall incidence is slightly higher in females, after the age of 80 years it is more frequent in males. Both pemphigus vulgaris and bullous pemphigoid has a chronic course with recurrences. Mortality risk of the patients with bullous pemphigoid was found at least 2 times higher and the mortality risk of the patients with pemphigus was found approximately 3 times higher than that of the general population. In this review, the results obtained from the epidemiological studies were analyzed according to geographic regions, and especially epidemiologic features of two prevalent autoimmune bullous diseases, pemphigus and bullous pemphigoid have been discussed.
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              A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid.

              Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease seen primarily in elderly persons. It is characterized clinically by the development of tense bullae and by the presence of an antibasement membrane antibody. In BP, the antigens involved in the autoimmunity are epidermal basement membrane peptides BPAg1 and BPAg2. We have compared high resolution typing of major histocompatibility complex class II loci (HLA-DRB1, DQB1) in 21 patients with BP, 17 with ocular cicatricial pemphigoid (OCP), and 22 with oral pemphigoid (OP) to a panel of 218 haplotypes of normal individuals. We found that the three diseases (BP, OCP, and OP) have significant association with DQB1*0301 (P = 0.005, P < 0.0001, and P = 0.001, respectively). The frequencies of alleles DQB1*0302, 0303, and 06, which share a specific amino acid sequence from position 71 to 77 (Thr-Arg-Ala-Glu-Leu-Val-Thr) were also increased (P = 0.01). We suggest that an identical major histocompatibility complex class II allele (DQB1*0301) is a common marker for enhanced susceptibility and that the same amino acid residues in positions 71-77 (DQB1*0301, -0302, -0305, -0602, -0603 alleles) are found in patients with BP, OCP and OP. Our findings propose that the autoimmune response in the three different clinical variants of pemphigoid, involves the recognition by T cells of a class II region of DQB1, bound to a peptide from the basement membrane of conjunctiva, oral mucosa, and skin.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                15 November 2016
                2016
                : 6
                : 37125
                Affiliations
                [1 ]PEDEGO Research Unit, University of Oulu; Department of Dermatology and Medical Research Center Oulu, Oulu University Hospital, P.O. Box 20, 90029 Oulu University Hospital , Oulu, Finland
                [2 ]Unit of General Practice, P.O. Box 10, 90029 Oulu University Hospital , Oulu, Finland
                [3 ]Center for Life Course Epidemiology and Systems Medicine, P.O. Box 5000, 90014, University of Oulu , Oulu, Finland
                [4 ]Research Unit of Clinical Neuroscience, University of Oulu; Department of Neurology and Medical Research Center Oulu, Oulu University Hospital, P.O. Box 5000, 90014, University of Oulu , Oulu, Finland
                [5 ]Psychoses and Forensic Psychiatry, Helsinki University Hospital, Vanha Valtatie 198, 04500, Kellokoski, Finland and Vanha Vaasa Hospital , Vierinkiventie 1, 65380 Vaasa, Finland
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep37125
                10.1038/srep37125
                5109264
                27845416
                3bca7151-9290-4bf8-99cc-2ced8574cae9
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 06 September 2016
                : 24 October 2016
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