Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid

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1 DOI /s REVIEW Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid Erkan Alpsoy Ayse Akman-Karakas Soner Uzun Received: 18 July 2014 / Revised: 11 November 2014 / Accepted: 29 November 2014 Ó Springer-Verlag Berlin Heidelberg 2015 Abstract Autoimmune bullous diseases are rare, organspecific, 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. E. Alpsoy (&) A. Akman-Karakas S. Uzun Department of Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey ealpsoy@akdeniz.edu.tr Keywords Autoimmune bullous diseases Pemphigus Bullous pemphigoid Epidemiology Introduction Autoimmune bullous diseases (ABD) are rare, organ-specific, a group of blistering disease of skin and mucous membranes mediated by autoantibodies directed against the desmosomes and hemidesmosomes. Pemphigus and bullous pemphigoid (BP) are the most prevalent ABD. Pemphigus encompasses a group of autoimmune intraepidermal blistering diseases classically divided into two major variants: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus are rarer forms. The pemphigoid group represents a group of autoimmune disorders characterized by subepidermal blistering. This group includes mainly BP, linear IgA disease, dermatitis herpetiformis, and epidermolysis bullosa acquisita. ABD run a chronic course and are associated with significant morbidity and even mortality. Our knowledge about the epidemiology of these diseases is still limited. ABD are reported from all around the world. When the epidemiological data are reviewed, clear regional differences are observed. Data regarding this group of disease are mostly as a reflection of the hospital records (frequently of university or teaching hospitals) with retrospective study design. The number of studies performed with the prospective study design which is more realistic choice of research methodology when assessing the frequency of ABD have been increasing in recent years. Two recent studies performed with prospective study design highlight information about the frequency of ABD in population. Marazza et al. [44] from Switzerland,

2 reported the incidence of ABD as 14.5/million/year. Bertram et al. [13] found this rate as 20.4/million/year for Germany. Recent data suggest that the frequency of the subepidermal ABD has been increasing. Zillikens et al. [70] from Germany reported the incidence of BP as 6.6/ million/year in Bertram et al. [13] reported this rate as 13.4/million/year in a recent study that they performed in a similar area in Germany. The large parts of the current studies regarding the ABD are about PV and BP. In this review we focused, therefore, on the epidemiological data of these diseases and tried to summarize main geographic differences of both diseases. Pemphigus Incidence Pemphigus incidence, in general, varies according to geographic area and ethnic groups (Table 1). The incidences reported from the different regions of Europe range between 0.5 and 8/million. The yearly pemphigus incidences reported from the Northern Europe such as Finland (0.76/million) [29], and Western Europe such as Germany ( /million) [13, 28], Switzerland (0.6/million) [44] and France (1.7/million) [10] are lower when compared to the other countries. Interestingly, in the study of Langan et al. [38] from UK, the incidence was reported with a notably high frequency when compared to the other Northern European countries with 6.8/million. In this study, the data was obtained from a computerized longitudinal general practice database (Health Improvement Network Database). Thus, the data may not be safe enough and more than one data entry may have been made for the same patient. In Greece [47], Italy [46], Macedonia [65], Serbia [26] located in the Southern Europe and Romania [7], Bulgaria [61], located in the Eastern Europe, the frequency of the disease is higher and ranges between 4 and 8/million. In the study of Uzun et al. [62] from the Mediterranean region of Turkey which is geographically closer to countries above, the yearly incidence of pemphigus is reported as 2.4/million. When the remaining parts of the world are reviewed, the yearly incidence in Asian countries varies between 1.6 and 16.1/million [16, 30, 37, 49, 53, 56, 60]. The highest frequency in this region was reported from Israel with 16.1/ million [53]. As is known, although pemphigus could be seen in all ethnical groups and races, it is more common among Askhenazis, which is one of the biggest two Jewish branch and people with Mediterranean roots. In the study of Simon et al. [58] from North America, the frequency of the disease was reported as 32/million in people with Jewish roots and 4.2/million in people from other ethnical races. In three studies performed in Africa, the yearly incidence of pemphigus was reported as 2.9/million in Mali [43] and 6.7 [10] and 8.62/million in Tunisia [69] (Table 1). In general, PV is the most frequently reported clinical subtype among the pemphigus group. When the epidemiologic data are reviewed, it is seen that at least 2/3 of the patients are diagnosed as PV. In our study [62], 83.1 % of the patients with pemphigus had the diagnosis of PV, 8.8 % of them had PF, 4 % had pemphigus erythematosus, 2.7 % had pemphigus herpetiformis and 0.7 % had pemphigus vegetans. While PF is seen all around the world sporadically, its endemic form (fogo selvagem) is seen in Brazil. This form of the disease is frequent in the rural and tropical regions in Brazil. In these regions, PF is approximately 20 times more frequent than PV. The frequency of the disease has been reported almost 3 % in some parts of Brazil [19]. The number of the new cases increases with the end of the rainy season. The disease is more frequently seen among those people who live in the riverside and whose economic conditions are poor and it is rarely reported from the urban areas. Again, in people who immigrated to the regions having a better hygienic condition, the disease tends to get better. Peru, Colombia, Algeria and Tunisia are countries where PF is frequently seen. This form of pemphigus is more frequent in the adolescence or around 20 years of age [45]. Therefore, PF was reported to outnumber PV in Brasil and other Latin American countries, and some African countries such as Mali and Tunisia [10]. On the other hand, Zaraa et al. [69] recently reported that although PF was relatively more prevalent especially in central and south part of their country, PV (%61) was more prevalent than PF (%36) in north Tunisia. Benchikhi et al. [11] from Morocco reported equal frequency of PF and PV, and Hietanen et al. [29] from Finland reported pemphigus erythematosus as the predominant form of pemphigus. In the study of Aboobaker et al. [1] from South Africa, PF was reported to be the most frequent pemphigus variant. The disease was especially frequent in black people, while most Indian cases with pemphigus presented with the PV subtype. Age and sex Pemphigus may occur in all age groups. When the Table 1 is reviewed, it is seen that the disease is most frequently diagnosed between the ages 40 and 60. While the mean age is between the ages of 50 and 60 in European countries, in the remaining countries in the world, it is between the ages of 30 and 50. Pemphigus has been reported more frequently in the females. The female male ratio varies between 0.45 and 5. Interestingly, male dominance has been reported so

3 Table 1 Demographic findings and incidences of pemphigus patients References Study design Country Continent Patient (n) Sex (F/M) Mean age (year) Incidence (cases/million) Bertram et al. [13] a Prospective Germany Europe Hahn-Ristic et al. [28] a Retrospective Germany Europe Hietanen et al. [29] Retrospective Finland Europe Marazza et al. [44] Prospective Switzerland Europe Langan et al. [38] a Retrospective UK Europe Bastuji-Garin et al. [10] Retrospective France Europe Micali et al. [46] Retrospective Italy Europe Michailidou et al. [47] a Retrospective Greece Europe V lckova-laskoska et al. [65] Retrospective Macedonia Europe Tsankov et al. [61] Retrospective Bulgaria Europe Golusin et al. [26] Retrospective Serbia Europe Baican et al. [7] Prospective Romania Europe Uzun et al. [62] Retrospective Turkey Europe Simon et al. [58] Retrospective USA North America (Jewish) 4.2 (Others) Tallab et al. [60] Retrospective Saudi Arabia Asia Salmanpour et al. [56] Retrospective Iran Asia Chams-Davatchi et al. [16] Prospective Iran Asia (Iran) 16 (Tehran) Kumar [37] Prospective India Asia (F), 58 (M) 4.4 Pisanti et al. [53] a Prospective Israel Asia Nanda et al. [49] Retrospective Kuwait Asia Huang et al. [30] a Prospective Taiwan Asia Mahé et al. [43] Retrospective Mali Africa Bastuji-Garin et al. [10] Retrospective Tunisia Africa Zaraa et al. [69] Retrospective Tunisia Africa a Studies including only pemphigus vulgaris patients far from some Middle Eastern countries such as Saudi Arabia [60], Kuwait [49], and Bangladesh [6] and China [32]. Mortality The disease has a long-term course, and is still associated with severe morbidity and considerable mortality. The mortality rate of pemphigus was very high until the 1950s. If pemphigus is left untreated, during 2 years the mortality is 50 % and at the end of 5 years, it is nearly 100 % [48]. The mortality rate has prominently decreased with the usage of corticosteroids in treatment. Although several effective treatments currently exist, none of them result in a cure of the disease. Therefore, pemphigus is still an important cause of significant mortality. There is relatively little data about the mortality rate and specific causes of mortality among patients with pemphigus compared with general population. Most of the previous data are hospitalbased and show a relatively high mortality rates ranging in the literature 5 15 % during various lengths of follow-up [48]. In our series [62], the follow-up period varied between 2 months and 6 years and during this period, 5 PV patient in total died from septicemia (3 patients), myocardial infarction (1 patient) and with unknown causes (1 patient). Recent population-based cohort studies by Langan et al. [38] from UK and Huang et al. [30] from Taiwan have given important epidemiologic data in this field. Langan et al. [38] found that the age- and gender-adjusted mortality rate was 3.3 times higher than that of controls. Huang et al. [30] reported that pemphigus patients have a 2.36-fold increase in mortality compared with the general population. Systemic and respiratory tract infections, cardiovascular disease, and peptic ulcer were the most common events leading to death. Huang et al. [30] also pointed out that patients with pemphigus onset after the age 60 years had worse prognoses and poorer survival rates compared with those whose disease onset was before 60 years age. This finding is in line with the previous data. Mortality rates can vary in different studies according to the countries health care systems where the study is performed, therefore they should be evaluated cautiously.

4 Associated diseases Pemphigus has been reported to be associated with other autoimmune diseases including autoimmune thyroid diseases namely, Graves disease and Hashimoto s thyroiditis [40], myasthenia gravis [31], Sjogren s disease, and rheumatoid arthritis [24]. Although, in a previous study Firooz et al. [25] found thyroid disease, type 1 diabetes mellitus and juvenile rheumatoid arthritis to be significantly more common in the family members of PV patients than in a control group, a recent study did not confirm these results. In the study of Leshem et al. [40] first-degree relatives of patients with pemphigus did not have a higher prevalence of autoimmune diseases than the general population. Oral lesions are a hallmark of PV and occur in almost all cases, and represent the preliminary symptom in more than half of the patients. Persistent lesions lead to lack of effective oral hygiene, and more plaque accumulation may increase the risk of long-term periodontal disease. Our recent study detected the periodontal disease at a higher frequency in the patients with pemphigus when compared to the control group [5]. The results indicate that PV might contribute to the development and/or progression of periodontitis. This observation may also be due to the difficulty to perform dental hygiene rather than the autoimmune disease being a precipitating factor. Triggering factors Drugs seems to be the most common cause of the outbreak of pemphigus. Thiol drugs (e.g., penicillamine, captopril, penicillin, cephalosporins), phenol drugs (e.g., cephalosporins, aspirin, rifampin, levodopa), and others (e.g., ACE inhibitors, NSAID, nifedipine) are the most commonly reported agents. Besides drugs, viral infections such as herpesvirus infections, physical agents such as ultraviolet radiation, contact allergens, diet, and smoking have also been noted to be important environmental factors triggering pemphigus [55]. However, the portion of patients in whom a particular triggering factor can be identified is small. Of note, V lckova-laskoska et al. [65] from Macedonia reported an epidemiological peak in 2001 during the local armed conflict. Women had a statistically significant increase in the incidence of the disease. They speculated that war-related elevated stress could be responsible for this deviation in the disease incidence. All these factors might trigger the disease by either modifying the immune response or altering the antigenic properties of the epidermal basement membrane and the outbreak of disease symptoms may regress after the triggering factor/s have been eliminated even in the absence of any treatment. On the other hand, findings suggest that tobacco smoking may confer some protective effects and mitigate pemphigus. The rate of smoking, both current and former was found significantly lower in pemphigus patients compared to age-matched controls [15, 59]. HLA A genetic susceptibility associated with the HLA types has been well documented in several populations. Furthermore, population studies of patients with pemphigus and its subtypes have shown that there are similarities among the most prevalent alleles in various ethnic groups. For the first time, Krain et al. [36] reported the increased frequency of HLA-A*10 in Ashkenazi Jewish people. Regarding the pemphigus, a strong association with HLA-DRB1*04, DRB1*14 and DQB1*05 from HLA class II antigens have been reported in the literature. HLA-DRB1*04 is seen especially in Ashkenazi Jewish patients. HLA-DRB1*14 has been more frequently reported in European and American Caucasians, Japanese, Chinese, Mexican, India and Pakistani populations [3, 4, 21, 23, 52, 63]. In our recent controlled study [35], distribution of HLA class I and II antigens in Turkish patients with pemphigus was evaluated. The frequencies of HLA-A*11, -CW*01, -DRB1*04, -DRB1*14, -DQB1*05 and -DPB1*0401 antigens in the disease group were found to be statistically higher compared to those of controls. Our results suggest that besides carrying common Class II HLA antigens for the genetic background of the pemphigus, Class I HLA antigens namely HLA-A*11, CW*01 are also associated with pemphigus in Southern Turkey. Furthermore, we observed differences in linkage disequilibrium pattern between patients and controls. Taking these factors together, we concluded that the coexistence of the respected antigens is strongly determinative for the predisposition (DRB1*14/DQB1*05 and A*11/DQB1*05) or protective (HLA-B*50/DQB1*02) against the disease. Bullous pemphigoid Incidence The large part of the data regarding the subepidermal ABD is about the BP, which is the most frequent disease among this group. The incidence of all subepidermal ABD was reported to be 19.9/million in the study of Bertram et al. [13] from Germany. As expected, BP was the most frequent subgroup (approximately 2/3 of all subepidermal ABD). The yearly incidences reported from Europe varies between 2.5 and 42.8/million [12, 18, 27, 33, 34, 57, 66, 70]. In some European countries, there are more than one

5 epidemiological data which were performed at different times. Among the studies performed in Germany at similar [34, 70] and in France [12, 33] at different regions, BP incidence is higher in the more recent ones. In a recent study of Joly et al. [33] the annual incidence of BP was estimated at 21.7 cases per million persons per year during the period for three French regions. It was about threefold higher than the incidence that previously estimated by Bernard et al. [12] during the period for three French regions with similar demographic characteristics and that reported by Zillikens et al. [70] in Germany during the same period. The highest incidence reported from Europe is the study of Langan et al. from UK [38]. In this study, just as in pemphigus the BP incidence was reported with a quite higher frequency (42.8/million) when compared to the other European countries. Although the limitation regarding the method of this study was discussed in the previous parts of the review an increase in the age of their populations can be speculated as one of the major causes for the raise in the incidence of BP observed both in France and the UK over the last 15 years. Joly et al. [33] suggested that increased incidence of dementia and other disabling neurological disorders which are major risk factors for BP among elderly patients, the increasing use of some drugs such as diuretics and psycholeptics and recently described clinical variants of BP which were not recognized in the past might be other possible explanations of the raise in the incidence of BP. On the other hand, the lowest frequency reported from Europe (2.5/million) belongs to the study of Baican et al. [7] from Romania. As previously mentioned, in this study pemphigus was reported to be the most frequently observed ABD (Table 2. The yearly BP incidences reported from Asian countries are: 2.6/million for Kuwait [49], and 7.6/million for Singapore [67]. A very high incidence of BP in infancy was reported by a study from Israel [66]. The incidence of BP in the Israeli population of infants under age of 1 during the study period was 23.6/million. Increased frequency of BP alongside with pemphigus in Israel shows that the genetic factors may play an important role in both disease groups (Table 2). However, as emphasized by authors, because of the relatively short period of time (3 years) of this study, the calculated incidence rates may reflect a chance in Israeli population over longer of periods time [66]. On the other hand, there is only one study from the remaining part of the World on the yearly BP incidences. In central and south part of Tunisia from the Africa countries, Zaraa et al. [69] recently reported the incidence of BP as Age and sex The incidence of BP increases sharply with age and it is most prevalent among elderly people. In the study of Marazza et al. [44] BP frequency increased after the age of 70 and had the highest frequency above the age of 90. Bertram et al. [13] reported the incidence of the disease Table 2 Demographic findings and incidences of bullous pemphigoid References Study design Country Continent Patient (n) Sex (F/M) Mean age (year) Incidence Serwin et al. [57] Prospective Poland Europe (F), (M) Jung et al. [34] Retrospective Germany Europe (F), (M) Zillikens et al. [70] Prospective Germany Europe Bernard et al. [12] Prospective France Europe Joly et al. [33] Retrospective France Europe Cozzani et al. [18] Prospective Italy Europe Bertram et al. [13] Prospective Germany Europe Gudi et al. [27] Retrospective Scotland Europe Langan et al. [38] Retrospective UK Europe Baican et al. [7] Prospective Romania Europe Marazza et al. [44] Prospective Switzerland Europe Uzun et al. [62] Prospective Turkey Europe Wong and Chua Retrospective Singapore Asia [67] Nanda et al. [49] Retrospective Kuwait Asia Waisbourd-Zinman Retrospective Israel Asia et al. [66] Zaraa et al. [69] Retrospective Tunisia Africa

6 above the age of 80 as 189/million/year. While Joly et al. [33] reported the incidence in the population aged 85 years or above as 507/million/year, Jung et al. [34] reported the incidence above the age of 90 as 485/million/year. In the study of Jung et al. [34] the risk of having BP after the age of 90 was calculated almost as 300 times higher when compared to the patients at the age of 60 and younger. These recent data shows that BP should not be considered as a rare disease in the elderly especially in European countries which have more elderly population. Interestingly, Bourdon-Lanoy et al. [14] from France reported that BP among young people is more severe and more active than the usual form in the elderly. BP was reported more frequently among females than males in all studies except the study of Zaraa et al. [69] from Tunisia. In the studies of Marazza et al. [44] and Joly et al. [33] the overall incidence was higher in females (yearly incidences 13.3/million and 25.7/million in females, and 10.6/million and 17.5/millions in males, respectively). However, above the age of 80 years BP was more frequent in males. When demographic data of the studies are reviewed, it can be seen that female and male ratio varies between 0.64 and 5.1 (Table 2). However, BP incidence in females is only slightly higher as in males. For the estimation of sex distributions in BP, the incidence of males and females in the general population has to be taken into account. This is particularly relevant, since BP is a disease of the elderly and the percentage of females tend to increase dramatically in the elderly population. Mortality In most cases, BP has a chronic course with recurrences. Despite recent improvements in BP treatment, it has a significant morbidity and mortality risk. In the literature, the mortality rate of BP is quite variable. Colbert et al. [17] found the yearly mortality rate in US to be 6 %. The same rate was reported as 41 % by Roujeau et al. [54] from France. The study of Joly et al. [33] in France showed a major excess of mortality in BP patients. The mortality rate of BP patients was more than sixfold higher than that in the general population of same age and sex composition. Langan et al. [38] reported the mortality risk of BP patients in UK as approximately twofold higher. The poor prognosis of BP is largely due to old age, side effects of treatment and associated other medical conditions. Associated diseases Among the conditions associated with BP, neurological, cardiovascular diseases and malignancy are those which are emphasized the most. Association of BP with malignancy or male patients with BP and malignancy has been reported and it was considered as a marker of malignancy. However, in the study of Lindelöf et al. [41] with 497 cases, which is the largest series in this respect, no association between BP and malignancy was detected. In a recent study, Ong et al. [51] conducted a nationwide record-linked study using national English hospital admission and mortality dataset for all public hospitals in England between 1999 and They found no evidence of increased risk of BP in people with cancer overall, and no evidence of increased risk of cancer overall in people with BP when compared with a reference cohort. Triggering factors BP may also occur due to drugs. Especially diuretics, analgesics, D-penicillamine, antibiotics and captopril are reported to be cause of BP [39]. Bastuji-Garin et al. [8], conducted a multicenter prospective case control study looking at the drugs used on a long-term basis before the onset of the disease in 116 incident cases of BP. Two classes of drugs, neuroleptics and diuretics (aldosterone antagonists), were reported more frequently in BP patients than control patients. Recently, Bastuji-Garin et al. [9] revisited the issue with a multicenter case control study, and evaluated the risk factors for BP in 201 incident BP cases. In a multivariate analysis, they identified chronic use of spironolactone or phenothiazines to be independently associated with BP besides major cognitive impairment, bedridden condition, Parkinson s disease, and unipolar or bipolar disorder. Physical agents (e.g., radiation therapy, ultraviolet radiation, thermal or electrical burns, surgical procedures, transplants) and infections, in particular human herpes virus infections (cytomegalovirus, Epstein Barr virus, and HHV-6) have also been suggested as possible triggering factors of BP in some cases [42]. It is wise to keep in mind that a great majority of cases with BP occur apparently without any obvious triggering factor. Venning and Wojnarowska [64] reported the prevalence of a recognizable triggering factor for BP in no more than 15 % of patients. HLA HLA-DQB1*0301 antigen seems to be associated with BP in Caucasians [22]. DRB1*04, DRB1*1101 and DQB1*0302 antigens have been reported to be associated with enhanced susceptibility to BP in Japanese society [50, 68]. Increased prevalence of BP in a specific geographical area was not noted.

7 In conclusion, pemphigus and BP are rare diseases and the yearly worldwide incidence of pemphigus and BP according to geographic region varies between 0.5 and 16.1 cases per million and cases per million, respectively. Among the pemphigus group, PV is the most frequently seen clinical subtype usually occurring between the ages of in Europe and in the remaining countries in the World (Table 1). BP being the most commonly observed subepidermal ABD is a typical elderly disease and it is most frequently seen after the age of 70. BP is reported to be the most prevalent ABD in Western [13, 44] and Northern Europe [38], and Singapore [67]. On the other hand, pemphigus is notified to be the commonest ABD in Romania [7], Turkey [62], Iran [20], China [32], Malaysia [2], Kuwait [49], and Tunisia [69]. BP relatively has a benign course compared with PV and at least some clinical forms respond more readily to low to mild doses of systemic and/or even topical corticosteroids. 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