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Autoimmune Blistering Diseases: Incidence and Treatment in Croatia
Autoimmune Blistering Diseases: Incidence and Treatment in Croatia Branka Marinovic, MD, PhD*, Jasna Lipozencic, MD, PhD, Ines Lakos Jukic, MD, MSc KEYWORDS Autoimmune blistering diseases Croatia Dermatovenereology Pemphigus
of the University of Zagreb School of Medicine. To the best of the authors’ knowledge, it is only at this department in Zagreb that the complete diagnostic algorithm of AIBD is performed (histopathology, immunofluorescence studies, and ELISA).1–4 The Department of Dermatology and Venereology, University Hospital Centre Zagreb also has a specific unit for children, which has been appointed a national referral center for epidermolysis bullosa by the Ministry of Health and Social Welfare of the Republic of Croatia. Hence, that department is a center of expertise in blistering diseases. The authors have analyzed patient records from the department from 2005 to 2010. In that period of time, the authors diagnosed 41 new pemphigus cases and 44 new pemphigoid cases. As indicated previously, patients from Northern and Eastern Croatia gravitate to Zagreb, so there is an estimated population of 2.2 million inhabitants. According to these data, the annual incidence for the pemphigus group of diseases is 3.7 new cases per million and 4 new cases of the pemphigoid group of diseases per million. In the pemphigus group of patients, 27 (66%) were women and 14 (34%) were men. In the pemphigoid group of patients, there were 23 (52%) women and 21 (48%) men. In the Dalmatian region of Croatia, on the eastern Adriatic coast, which is part of the Mediterranean, in the same period of time, there were 14 new pemphigus cases and 20 new pemphigoid cases. Because the estimated population
Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Salata 4, 10000 Zagreb, Croatia * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 677–679 doi:10.1016/j.det.2011.07.003 0733-8635/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
derm.theclinics.com
The Republic of Croatia is a country laying in Central and Southeastern Europe, at the crossroads of the Pannonian Plain, the Balkans, and the Adriatic Sea. Croatia borders Slovenia to the north, Hungary to the northeast, Bosnia and Herzegovina to the southeast, Serbia to the east, and Montenegro to the southeast (Fig. 1). The population of Croatia is estimated to be 4.5 million inhabitants, with 1.2 million of them living in Zagreb, the capital of Croatia. Dermatovenereology in Croatia has a long tradition, with the first Department of Dermatovenereology in Croatia having opened in Zagreb in 1894. Because Croatia was a part of the Austro-Hungarian Empire and because of its geographic location in Central Europe, approach to dermatovenereology is based on Central European dermatovenereology traditions, with treatment of many patients still on in-patient wards. There are 4 medical schools in Croatia (in Zagreb, Split, Rijeka, and Osijek) and 5 university departments of dermatovenereology (one of them is part of a school of dental medicine). In other towns in Croatia, some hospitals have dermatology units. If a diagnosis of autoimmune bullous disease (AIBD) is suspected, the patient is referred to one of the university departments because of their ability to establish the diagnosis. The diagnosis of AIBD is based on clinical, histopathologic, and immunopathologic findings. Most of the patients from Northern and Eastern Croatia are referred to the Department of Dermatology and Venereology
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Marinovic et al
Fig. 1. Map of Croatia.
of Dalmatia is 900,000, the annual incidence of the pemphigus group of diseases in this area is 3.1 per million and 4.4 new cases of pemphigoid group of diseases per million. The incidences of these two diseases are not dissimilar, given that in many countries, pemphigoid is more common than pemphigus. The life expectancy in Croatia for men is 71 years and for women is 78 years. Because pemphigoid predominantly affects the elderly population, the authors do not believe these patients are dying of other causes before the development of pemphigoid, which may occur in poorer countries. All laboratory procedures, including ELISA for detecting autoantibodies against desmoglein 1, desmoglein 3, BP180, BP230, and tissue and epidermal transglutaminase, are covered by obligatory health insurance possessed by all Croatian citizens. Sera from patients who have been hospitalized in other university departments are referred to the Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb for ELISA testing. After a diagnosis of AIBD is established, the treatment is started. Almost all patients with the pemphigus group of diseases and the majority of patients with the pemphigoid group of diseases are hospitalized, which enables quick and complete assessment of patients’ overall medical status to identify risks of developing complications
from steroids and other systemic drugs. Patients with mild forms of pemphigoid are treated in the outpatient clinic. The standard therapy for the pemphigus group of diseases includes prednisone, usually 1 mg/kg (for pemphigus vulgaris). Azathioprine is usually given as adjuvant treatment, although there are some patients in whom mycophenolic acid is introduced. In refractory cases intravenous immunoglobulin is given. Plasmapheresis, an effective treatment, has been used for only a few patients. The authors have no experience with biologic drugs, such as rituximab, because of limited indications for this drug covered by health insurance companies. Patients with the pemphigoid group of diseases (bullous pemphigoid) are treated with corticosteroids, usually starting with prednisone (0.5 mg/kg) with accentuation of topical corticosteroid therapy. Only a few refractory patients have been on adjuvant therapy also. Patients with dermatitis herpetiformis Duhring and linear IgA dermatosis are initially treated with dapsone, but this drug has not been registered in Croatia, so patients have to buy it themselves. After control of AIBD is achieved, patients are released from the department and then regularly controlled and carefully followed up in the outpatient clinic, usually monthly, with special attention to possible side effects of long-term corticosteroid therapy. All medications and procedures, which
Autoimmune Blistering Diseases in Croatia are recommended by a dermatologist, are prescribed by a competent general practitioner. Some of the most interesting cases cured and diagnosed in the Department were discussed and published in dermatologic journals.5–8 Unfortunately, there are no AIBD support groups in Croatia. Since 2007 the authors have been collecting data concerning patients with AIBD (a project supported by Ministry of Science of the Republic of Croatia) and are investigating the possible association of certain HLA class II alleles and haplotypes with pemphigus vulgaris in Croatia. The aim of this study is to analyze HLA associations and to investigate any differences between patients from central Croatia and those from Dalmatia. Future goals are to participate in multicenter studies because this is the only possibility for further investigation for these rare diseases.
REFERENCES 1. Marinovic B, Fabris Z, Lipozencic J, et al. Comparison of diagnostic value of indirect immunofluorescence assay and desmoglein ELISA in the diagnosis of pemphigus. Acta Dermatovenerol Croat 2010;18: 79–83.
2. Lakos Jukic I, Marinovic B. Sensitivity of indirect immunofluorescence test in the diagnosis of pemphigus. Acta Dermatovenerol Croat 2004;12:162–5. 3. Marinovic B, Lakos Jukic I. Autoimmune blistering diseases in childhood. Acta Dermatovenerol Croat 2002;10:33–7. 4. Ljubojevic S, Lipozencic J, Brenner S, et al. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol 2002;16:599–603. 5. Pastar Z, Rados J, Lipozencic J, et al. Case of concurrent epidermolysis bullosa acquisita and antip200 pemphigoid—how to treat it? Int J Dermatol 2007;46:295–8. 6. Marinovic B, Mokos Bukvic Z, Basta-Juzbasic A, et al. Atypical clinical appearance of pemphigus vulgaris on the face: case report. Acta Dermatovenerol Croat 2005;13:81–4. 7. Marinovic B, Basta-Juzbasic A, Bukvic Mokos Z, et al. Coexistence of pemphigus herpetiformis and systemic lupus erythematosus. J Eur Acad Dermatol Venereol 2003;17:316–9. 8. Pasic A, Ljubojevic S, Lipozencic J, et al. Coexistence of psoriasis vulgaris, bullous pemphigoid and vitiligo: a case report. J Eur Acad Dermatol Venereol 2002;16:426–7.
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of the University of Zagreb School of Medicine. To the best of the authors’ knowledge, it is only at this department in Zagreb that the complete diagnostic algorithm of AIBD is performed (histopathology, immunofluorescence studies, and ELISA).1–4 The Department of Dermatology and Venereology, University Hospital Centre Zagreb also has a specific unit for children, which has been appointed a national referral center for epidermolysis bullosa by the Ministry of Health and Social Welfare of the Republic of Croatia. Hence, that department is a center of expertise in blistering diseases. The authors have analyzed patient records from the department from 2005 to 2010. In that period of time, the authors diagnosed 41 new pemphigus cases and 44 new pemphigoid cases. As indicated previously, patients from Northern and Eastern Croatia gravitate to Zagreb, so there is an estimated population of 2.2 million inhabitants. According to these data, the annual incidence for the pemphigus group of diseases is 3.7 new cases per million and 4 new cases of the pemphigoid group of diseases per million. In the pemphigus group of patients, 27 (66%) were women and 14 (34%) were men. In the pemphigoid group of patients, there were 23 (52%) women and 21 (48%) men. In the Dalmatian region of Croatia, on the eastern Adriatic coast, which is part of the Mediterranean, in the same period of time, there were 14 new pemphigus cases and 20 new pemphigoid cases. Because the estimated population
Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Salata 4, 10000 Zagreb, Croatia * Corresponding author. E-mail address: [email protected] Dermatol Clin 29 (2011) 677–679 doi:10.1016/j.det.2011.07.003 0733-8635/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
derm.theclinics.com
The Republic of Croatia is a country laying in Central and Southeastern Europe, at the crossroads of the Pannonian Plain, the Balkans, and the Adriatic Sea. Croatia borders Slovenia to the north, Hungary to the northeast, Bosnia and Herzegovina to the southeast, Serbia to the east, and Montenegro to the southeast (Fig. 1). The population of Croatia is estimated to be 4.5 million inhabitants, with 1.2 million of them living in Zagreb, the capital of Croatia. Dermatovenereology in Croatia has a long tradition, with the first Department of Dermatovenereology in Croatia having opened in Zagreb in 1894. Because Croatia was a part of the Austro-Hungarian Empire and because of its geographic location in Central Europe, approach to dermatovenereology is based on Central European dermatovenereology traditions, with treatment of many patients still on in-patient wards. There are 4 medical schools in Croatia (in Zagreb, Split, Rijeka, and Osijek) and 5 university departments of dermatovenereology (one of them is part of a school of dental medicine). In other towns in Croatia, some hospitals have dermatology units. If a diagnosis of autoimmune bullous disease (AIBD) is suspected, the patient is referred to one of the university departments because of their ability to establish the diagnosis. The diagnosis of AIBD is based on clinical, histopathologic, and immunopathologic findings. Most of the patients from Northern and Eastern Croatia are referred to the Department of Dermatology and Venereology
678
Marinovic et al
Fig. 1. Map of Croatia.
of Dalmatia is 900,000, the annual incidence of the pemphigus group of diseases in this area is 3.1 per million and 4.4 new cases of pemphigoid group of diseases per million. The incidences of these two diseases are not dissimilar, given that in many countries, pemphigoid is more common than pemphigus. The life expectancy in Croatia for men is 71 years and for women is 78 years. Because pemphigoid predominantly affects the elderly population, the authors do not believe these patients are dying of other causes before the development of pemphigoid, which may occur in poorer countries. All laboratory procedures, including ELISA for detecting autoantibodies against desmoglein 1, desmoglein 3, BP180, BP230, and tissue and epidermal transglutaminase, are covered by obligatory health insurance possessed by all Croatian citizens. Sera from patients who have been hospitalized in other university departments are referred to the Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb for ELISA testing. After a diagnosis of AIBD is established, the treatment is started. Almost all patients with the pemphigus group of diseases and the majority of patients with the pemphigoid group of diseases are hospitalized, which enables quick and complete assessment of patients’ overall medical status to identify risks of developing complications
from steroids and other systemic drugs. Patients with mild forms of pemphigoid are treated in the outpatient clinic. The standard therapy for the pemphigus group of diseases includes prednisone, usually 1 mg/kg (for pemphigus vulgaris). Azathioprine is usually given as adjuvant treatment, although there are some patients in whom mycophenolic acid is introduced. In refractory cases intravenous immunoglobulin is given. Plasmapheresis, an effective treatment, has been used for only a few patients. The authors have no experience with biologic drugs, such as rituximab, because of limited indications for this drug covered by health insurance companies. Patients with the pemphigoid group of diseases (bullous pemphigoid) are treated with corticosteroids, usually starting with prednisone (0.5 mg/kg) with accentuation of topical corticosteroid therapy. Only a few refractory patients have been on adjuvant therapy also. Patients with dermatitis herpetiformis Duhring and linear IgA dermatosis are initially treated with dapsone, but this drug has not been registered in Croatia, so patients have to buy it themselves. After control of AIBD is achieved, patients are released from the department and then regularly controlled and carefully followed up in the outpatient clinic, usually monthly, with special attention to possible side effects of long-term corticosteroid therapy. All medications and procedures, which
Autoimmune Blistering Diseases in Croatia are recommended by a dermatologist, are prescribed by a competent general practitioner. Some of the most interesting cases cured and diagnosed in the Department were discussed and published in dermatologic journals.5–8 Unfortunately, there are no AIBD support groups in Croatia. Since 2007 the authors have been collecting data concerning patients with AIBD (a project supported by Ministry of Science of the Republic of Croatia) and are investigating the possible association of certain HLA class II alleles and haplotypes with pemphigus vulgaris in Croatia. The aim of this study is to analyze HLA associations and to investigate any differences between patients from central Croatia and those from Dalmatia. Future goals are to participate in multicenter studies because this is the only possibility for further investigation for these rare diseases.
REFERENCES 1. Marinovic B, Fabris Z, Lipozencic J, et al. Comparison of diagnostic value of indirect immunofluorescence assay and desmoglein ELISA in the diagnosis of pemphigus. Acta Dermatovenerol Croat 2010;18: 79–83.
2. Lakos Jukic I, Marinovic B. Sensitivity of indirect immunofluorescence test in the diagnosis of pemphigus. Acta Dermatovenerol Croat 2004;12:162–5. 3. Marinovic B, Lakos Jukic I. Autoimmune blistering diseases in childhood. Acta Dermatovenerol Croat 2002;10:33–7. 4. Ljubojevic S, Lipozencic J, Brenner S, et al. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol 2002;16:599–603. 5. Pastar Z, Rados J, Lipozencic J, et al. Case of concurrent epidermolysis bullosa acquisita and antip200 pemphigoid—how to treat it? Int J Dermatol 2007;46:295–8. 6. Marinovic B, Mokos Bukvic Z, Basta-Juzbasic A, et al. Atypical clinical appearance of pemphigus vulgaris on the face: case report. Acta Dermatovenerol Croat 2005;13:81–4. 7. Marinovic B, Basta-Juzbasic A, Bukvic Mokos Z, et al. Coexistence of pemphigus herpetiformis and systemic lupus erythematosus. J Eur Acad Dermatol Venereol 2003;17:316–9. 8. Pasic A, Ljubojevic S, Lipozencic J, et al. Coexistence of psoriasis vulgaris, bullous pemphigoid and vitiligo: a case report. J Eur Acad Dermatol Venereol 2002;16:426–7.
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