Report
HLA DRB1* and DQB1* alleles are associated with disease severity in patients with pemphigus vulgaris Danka Svecova1, MD, PhD, Zuzana Parnicka2, MD, PhD, Lucia Pastyrikova1, MD, Slavomir Urbancek3, MD, PhD, Jan Luha4, RND, CSc, and Milan Buc2, MD, DrSc
1 Department of Dermatovenereology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, 2Institute of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, 3 Department of Dermatovenereology, Faculty of Medicine, Slovak Medical University, F. D. Roosvelt Hospital, Banska Bystrica, Slovakia, and 4Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
Correspondence Danka Svecova, MD, PhD Department of Dermatovenereology Faculty of Medicine Comenius University Mickiewiczova 13, 813 69 Bratislava Slovakia E-mail: [email protected] Funding: Research Program of the Ministry of Education, Slovak Republic (VEGA 1/0145/09). Conflicts of interest: None.
Abstract Background Pemphigus vulgaris (PV) is a rare autoimmune disease that involves the skin and mucosa. The etiology of PV is multifactorial and includes genetic, environmental, hormonal, and immunological factors. Objectives The purpose of this study was to examine the relationships between human leukocyte antigen (HLA) class II alleles associated with PV and variations in the disease phenotype. Methods Forty-four PV patients were diagnosed and analyzed at the Bullous Disorders Unit in cooperation with the Institute of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. HLA class II alleles previously found to be associated with PV (DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1*14:04, DRB1*14:05, DQB1*03:02 and DQB1*05:03) were analyzed according to disease severity, PV type, and gender distribution. Results Correlations emerged between PV severity scores and HLA alleles. The DRB1*04:02 and DQB1*03:02 alleles were associated with severe PV (P = 0.001); DRB1*04:02 was associated with the mucocutaneous type (P = 0.024), and DQB1*03:02 was found more frequently in female than in male patients (P = 0.016). Analyses of the other alleles did not reveal significant associations with the clinical parameters evaluated. Conclusions The HLA DRB1* and DQB1* alleles influence susceptibility to PV and may contribute to PV severity and type. These results suggest that genetic background may contribute to disease outcome by affecting the disease course and efficacy of treatment because some of the alleles were found significantly more frequently in patients with severe disease.
doi: 10.1111/ijd.12418
Introduction Pemphigus vulgaris (PV) is a rare but serious autoimmune disease that involves the skin and mucosa. Autoantibodies are directed against antigens, desmogleins (Dsg) 3 and 1, on the surface of keratinocytes. Desmogleins are keratinocyte transmembrane proteins localized in the desmosome, which is essential for keratinocyte–keratinocyte adhesion. The interaction of anti-Dsg autoantibodies with their target antigens is responsible for the loss of cell adhesion (acantholysis) and the formation of intraepithelial blisters of the skin and mucosa.1 Familial cases of PV involving first-degree relatives have only rarely been reported; however, a significant increase in the prevalence of autoimmune diseases in first-degree relatives of PV patients compared with relatives of healthy control subjects has been established.2,3 The detection of anti-Dsg3 ª 2014 The International Society of Dermatology
autoantibodies in asymptomatic first-degree relatives of PV patients predicts the involvement of genetic factors in PV.4,5 However, as with most autoimmune diseases, PV belongs to the family of polygenetic disorders with phenotypes that result from alterations in several different genes with additive or interacting effects. Pemphigus vulgaris is more prevalent in people of Mediterranean or Jewish ancestry.1 Associations between human leukocyte antigen (HLA) class II alleles and PV have been previously documented in populations of different ethnicities.1 Pemphigus vulgaris was found to be associated with DR4 and DR14, although the susceptibility gene is dependent on ethnic origin.6,7 In the Slovak population, we previously identified significant positive associations between PV and DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1 *14:04, DRB1*14:05, DQB1*03:02, and DQB1*05:03.8 Thus, the purpose of this study was to examine the International Journal of Dermatology 2014
1
2
Report
Svecova et al.
HLA alleles and disease severity in pemphigus
relationship between HLA class II alleles associated with PV and variations in the phenotype of PV. Materials and methods The study was performed in the Bullous Disorder Unit in the Department of Dermatovenereology, University Hospital of Comenius University in Bratislava, Slovakia, in cooperation with the Institute of Immunology, Faculty of Medicine, Comenius University. Forty-four unrelated Caucasian PV patients from various parts of Slovakia were investigated. This study was designed to uncover any association between HLA class II alleles and the severity of PV in Slovak patients. The PV patients were diagnosed based on clinical, histopathological, and direct immunofluorescence findings before enrollment in the study. HLA class II alleles were typed by polymerase chain reaction with sequence-specific primers (PCR-SSP) from our previous study. Commercially available primer kits (Olerup SSP DQ-DR Combi Tray; Olerup SSP AB,
Statistical analysis Data were compiled electronically using Excel and analyzed using IBM SPSS Statistics Version 20 (IBM Corp., Armonk, NY, USA). We used frequency tables for the statistical analysis of numerical variables, including the mean, median, confidence intervals (CIs), standard deviation (SD), minimum, maximum, and range. The different variables were calculated with 95% CIs. Normal distributions of the numerical data were obtained using the mean values and SDs. Numerical data with non-normal distributions were evaluated using the non-parametric Mann–Whitney U test for comparisons between two datasets, and the Kruskal–Wallis test was used for comparisons among more than two datasets. Associations between the categorized variables and outcomes were assessed using Fisher’s exact test. Statistical significance was defined by a P-value of 10 years had significantly higher anti-DsG3 IgG4 autoantibody levels than patients with a recent onset of disease within the past two years. These results remained significant only in patients with active disease and not in remittent patients. Additionally, in the same study, antiDsg3 IgG4 autoantibody levels were significantly higher in patients who carried one or both of the disease-associated HLA alleles (DRB1*04:02 and DQB1*05:03) than in carriers of other HLA alleles.15 In our previous study, we uncovered correlations between DRB1* and DQB1* alleles and clinical phenotypic variables in PV patients. Analysis of the DRB1* and DQB1* alleles with additional clinical parameters highlights the association of International Journal of Dermatology 2014
DRB1*04:02 alleles with severe PV (P = 0.031) and with the mucocutaneous type of PV (P = 0.024); further, the frequency of the alleles is greater than in carriers of other HLA alleles. Moreover, we documented an association of DQB1*03:02 alleles in patients with severe PV (P = 0.031) and in female patients (P = 0.016). These results are in concordance with our previous study, in which we documented more severe disease in female than in male PV patients. Simultaneously, we recorded a longer remission survival time in female PV patients compared with male PV patients.16 Furthermore, the presence of the DQB1*03:02 allele has been shown to be increased significantly in PV patients.6,11,14,17 Limited data indicate an association of DRB1*14:54 with PV, perhaps because this allele was included in DRB1*14:01 until 2005,18 although an association between DRB1*14:54 and PV patients has been reported.14 Likewise, we previously found an association of DRB1*14:54 and PV in PV patients.8 In the current ª 2014 The International Society of Dermatology
Svecova et al.
study, we found an association between DRB1*14:54 and PV only in our male patients (P = 0.047). We cannot, however, explain this association of DRB1*14:54 with gender. Moreover, the distribution of DRB1*14:54 was similar with regard to other evaluated clinical parameters and did not significantly differ between any other groups. Specific HLA-DR and HLA-DQ molecules may influence susceptibility or resistance to PV, and thus these alleles may, perhaps, contribute to the variability in clinical phenotypes in PV patients. We believe that DBR1* and DQB1* alleles may play a role in the pathogenesis and course of the disease. Likewise, these alleles may influence additional factors that contribute to the clinical heterogeneity of PV, including the heterogeneous susceptibility to various immunosuppressive drugs and the unpredictable disease course observed in PV patients. Several triggers, including infection, pregnancy, drug intake, diet, and sun exposure, are thought to evoke pemphigus.1 Furthermore, stress may influence the course of autoimmune disease,19 and stress was found to worsen the course of PV during local armed conflict in Macedonia.20 Despite this knowledge, the course of PV remains unpredictable; thus, the identification of factors that contribute to the course of the disease and its prognosis is highly desirable. In our recent study, we reported the finding of a poor prognosis in patients with multiple mucosal lesions, severe disease, and longer remission survival time, which was more frequently found in females than in males.16 Other authors have documented poor prognoses in PV patients aged ≤40 years with initial mucosal involvement.21 Finally, first relapse-free survival in PV with mucosal involvement was found to be a predictor of poor prognosis.22 HLA polymorphisms may provide genetic support for the variability in PV outcomes. Our previous study suggests that certain gene polymorphisms of various cytokines, including tumor necrosis factor-a and interleukin-10, may influence genetic susceptibility to PV and may contribute to the phenotypic variability of the disease.23 In concordance with previously reported studies,3,24 we found that 11.4% of first-degree relatives of PV patients suffered from autoimmune disease, including type 1 diabetes mellitus, rheumatoid arthritis, and thyroidal autoimmunity. The frequency of autoimmune disease is considered to be 5–7% in the general population.25 Multiple autoimmune disorders suggest that various conditions result from an abnormality in immune regulation and thus that clinically distinct autoimmune phenotypes may represent pleiotropic outcomes of a genetic trait, the manifestation of which may depend on complex interactions between genes and the environment.26 In concordance with these observations, 22.7% of PV patients in the present series had additional autoimmune disease, including thyroidal autoimmunity, rheumatoid arthritis, ulcerative colitis, vitiª 2014 The International Society of Dermatology
HLA alleles and disease severity in pemphigus
Report
ligo, and psoriasis. By contrast, another study found only 6.3% of PV patients documented concurrent autoimmune diseases, including autoimmune thyroid disease and rheumatoid arthritis, and 2.6% of first-degree relatives had autoimmune diseases.27 One limitation of the present study stems from its relatively small number of participants, which is attributable to the rarity of the disease. We appreciate the new ABSIS system, which provides a precise definition of the disease phenotype and allows for the comparison of results across various studies. Our results suggest that the HLA DRB1* and DQB1* alleles not only influence susceptibility to PV but may also contribute to the variable clinical phenotype of PV. Moreover, our studies indicate that genetic background may contribute to the outcome of the disease, including its unpredictable course and variability in treatment efficacy, because some of the alleles were present at significantly higher frequencies in patients with severe disease, who frequently experience these problems. In addition, in the present series, the mucocutaneous type of PV was found more frequently in patients with severe PV than in those with mild PV, and females exhibited severe disease more frequently than men. Conclusions Specific HLA DRB1*and DQB1* alleles may influence susceptibility to PV and, moreover, may contribute to the phenotypic variability of PV. We found DRB1*04:02 and DQB1*03:02 to be associated with severe PV. In addition, we identified a correlation between DRB1*04:02 and the mucocutaneous type of PV, and a correlation between the DQB1*03:02 allele and female gender. Moreover, our studies indicate that genetic background may contribute to the outcome of the disease, including its unpredictable course and variability in treatment efficacy, because some of the alleles were present at significantly higher frequencies in patients with severe disease. Other PV-associated DRB1* and DQB1* alleles, including DRB1*04, DRB1*14, and DQB1*05, were distributed without significant differences within all evaluated phenotypes of PV. Acknowledgments The authors thank Professor Jagienka Jautova, MD, PhD (Department of Dermatovenereology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia) and Eva Vrtikova, MD (Department of Dermatovenereology, Faculty of Medicine, Slovak Medical University, Nitra, Slovakia) for their cooperation, and BioMed Proofreading LLC (Cleveland, OH, USA) for Englishlanguage editing. International Journal of Dermatology 2014
5
6
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Svecova et al.
HLA alleles and disease severity in pemphigus
References 1 Svecova D. Pemphigus Bratislava: Bonus 2009: 23–46. 2 Meyer N, Misery L. Geoepidemiologic considerations of autoimmune pemphigus. Autoimmun Rev 2010; 9: 379–382. 3 Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 25: 1094–1108. 4 Kricheli D, David M, Frusic-Zlotkin M, et al. The distribution of pemphigus vulgaris-IgG subclasses and their reactivity with desmoglein 3 and 1 in pemphigus patients and their first-degree relatives. Br J Dermatol 2000; 143: 337–342. 5 Brandsen R, Frusic-Zlotkin M, Lyubimov H, et al. Circulating pemphigus IgG in families of patients with pemphigus: comparison of indirect immunofluorescence, direct immunofluorescence, and immunoblotting. J Am Acad Dermatol 1997; 36: 44–52. 6 Lee E, Lendas KA, Chow S, et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Hum Immunol 2006; 67: 125–139. 7 Yan L, Wang JM, Zeng K. Association between HLA-DRB1 polymorphisms and pemphigus vulgaris: a meta-analysis. Br J Dermatol 2012; 167: 768–777. 8 Parnicka Z, Svecov a D, Javor J, et al. High susceptibility to pemphigus vulgaris due to HLA-DRB1*14:54 in the Slovak population. Int J Dermatol 2013; 40: 471–475. 9 Sebaratnam D, Murrel D. Objective scoring system for disease activity in autoimmune bullous diseases. Dermatol Clin 2011; 29: 515–520. 10 Werth VP. Measuring extent and activity of disease in pemphigus. SYM-SO36, Educational Sessions Handouts, 69th Annual meeting of the American Academy of Dermatology, February 4–8, 2011, New Orleans, LA. 11 Carcassi C, Cottoni F, Floris L, et al. HLA haplotypes and class II molecular alleles in Sardinian and Italian patients with pemphigus vulgaris. Tissue Antigens 1996; 6: 662–667. 12 Loiseau P, Lecleach L, Prost C. HLA class II polymorphism contributes to specify desmoglein derived peptides in pemphigus vulgaris and pemphigus foliaceus. J Autoimmun 2000; 15: 67–73. 13 Gonzalez-Escribano MF, Jimenez G, Walter K. Distribution of HLA class alleles among Spanish patients with pemphigus vulgaris. Tissue Antigens 1998; 52: 275–278. 14 Saha M, Harman K, Mortimer NJ, et al. Pemphigus vulgaris in white Europeans is linked with HLA class II
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19 20
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allele HLA DRB*1454 but not DRB1*1401. J Invest Dermatol 2010; 130: 311–314. Dhandha MM, Seiffert-Sinha K, Sinha AA. Specific immunoglobulin isotypes correlate with disease activity, morphology, duration and HLA association in pemphigus vulgaris. Autoimmunity 2012; 45: 516–526. Svecova D. Pemphigus vulgaris: a clinical study of 44 cases over a 20-year period. Int J Dermatol 2013; 2014, In press. Shams S, Amirzargar AA, Yousefi M, et al. HLA class II (DRB, DQA1 and DQB1) allele and haplotype frequencies in the patients with pemphigus vulgaris. J Clin Immunol 2009; 29: 175–179. Marsh SGE, Albert ED, Bontrop RE, et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010; 75: 291–455. Stojanovich L. Stress and autoimmunity. Autoimmun Rev 2010; 9: 271–276. VIckova-Laskoska MT, Laskoski DS, Kamberova S, et al. Epidemiology of pemphigus in Macedonia: a 15-year retrospective study (1990–2004). Int J Dermatol 2007; 46: 253–258. Minouni D, Bar H, Gdalevich M, et al. Pemphigus, analysis of 155 patients. J Eur Acad Dermatol Venereol 2010; 24: 947–952. Khaled A, Taazayet SBBen Alaya N, et al. The course and prognosis of pemphigus in 47 Tunisian patients. J Eur Acad Dermatol Venereol 2013; 27: 81–85. Javor J, Chmurova N, Parnicka Z, et al. TNF-alpha and IL-10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population. J Eur Acad Dermatol Venereol 2010; 24: 65–68. Jacobson DL, Ganges SJ, Rose NR, et al. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–243. Buc M. Immunogenetic mechanisms in autoimmune process: disorders of immune regulatory mechanisms, genetic determination of autoimmunity, effector mechanisms of autoimmune processes and their therapy. Bratisl Lek Listy 1996; 97: 660–668. Prahalad S, Shear ES, Thompson SD, et al. Increased prevalence of familial autoimmunity in simplex and multiplex families with juvenile rheumatoid arthritis. Arthritis Rheum 2002; 46: 1851–1856. Leshem YA, Katzenelson V, Yosipovitch G, et al. Autoimmune disease in patients with pemphigus and their first-degree relatives. Int J Dermatol 2011; 50: 827–831.
ª 2014 The International Society of Dermatology
HLA DRB1* and DQB1* alleles are associated with disease severity in patients with pemphigus vulgaris Danka Svecova1, MD, PhD, Zuzana Parnicka2, MD, PhD, Lucia Pastyrikova1, MD, Slavomir Urbancek3, MD, PhD, Jan Luha4, RND, CSc, and Milan Buc2, MD, DrSc
1 Department of Dermatovenereology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, 2Institute of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, 3 Department of Dermatovenereology, Faculty of Medicine, Slovak Medical University, F. D. Roosvelt Hospital, Banska Bystrica, Slovakia, and 4Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
Correspondence Danka Svecova, MD, PhD Department of Dermatovenereology Faculty of Medicine Comenius University Mickiewiczova 13, 813 69 Bratislava Slovakia E-mail: [email protected] Funding: Research Program of the Ministry of Education, Slovak Republic (VEGA 1/0145/09). Conflicts of interest: None.
Abstract Background Pemphigus vulgaris (PV) is a rare autoimmune disease that involves the skin and mucosa. The etiology of PV is multifactorial and includes genetic, environmental, hormonal, and immunological factors. Objectives The purpose of this study was to examine the relationships between human leukocyte antigen (HLA) class II alleles associated with PV and variations in the disease phenotype. Methods Forty-four PV patients were diagnosed and analyzed at the Bullous Disorders Unit in cooperation with the Institute of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. HLA class II alleles previously found to be associated with PV (DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1*14:04, DRB1*14:05, DQB1*03:02 and DQB1*05:03) were analyzed according to disease severity, PV type, and gender distribution. Results Correlations emerged between PV severity scores and HLA alleles. The DRB1*04:02 and DQB1*03:02 alleles were associated with severe PV (P = 0.001); DRB1*04:02 was associated with the mucocutaneous type (P = 0.024), and DQB1*03:02 was found more frequently in female than in male patients (P = 0.016). Analyses of the other alleles did not reveal significant associations with the clinical parameters evaluated. Conclusions The HLA DRB1* and DQB1* alleles influence susceptibility to PV and may contribute to PV severity and type. These results suggest that genetic background may contribute to disease outcome by affecting the disease course and efficacy of treatment because some of the alleles were found significantly more frequently in patients with severe disease.
doi: 10.1111/ijd.12418
Introduction Pemphigus vulgaris (PV) is a rare but serious autoimmune disease that involves the skin and mucosa. Autoantibodies are directed against antigens, desmogleins (Dsg) 3 and 1, on the surface of keratinocytes. Desmogleins are keratinocyte transmembrane proteins localized in the desmosome, which is essential for keratinocyte–keratinocyte adhesion. The interaction of anti-Dsg autoantibodies with their target antigens is responsible for the loss of cell adhesion (acantholysis) and the formation of intraepithelial blisters of the skin and mucosa.1 Familial cases of PV involving first-degree relatives have only rarely been reported; however, a significant increase in the prevalence of autoimmune diseases in first-degree relatives of PV patients compared with relatives of healthy control subjects has been established.2,3 The detection of anti-Dsg3 ª 2014 The International Society of Dermatology
autoantibodies in asymptomatic first-degree relatives of PV patients predicts the involvement of genetic factors in PV.4,5 However, as with most autoimmune diseases, PV belongs to the family of polygenetic disorders with phenotypes that result from alterations in several different genes with additive or interacting effects. Pemphigus vulgaris is more prevalent in people of Mediterranean or Jewish ancestry.1 Associations between human leukocyte antigen (HLA) class II alleles and PV have been previously documented in populations of different ethnicities.1 Pemphigus vulgaris was found to be associated with DR4 and DR14, although the susceptibility gene is dependent on ethnic origin.6,7 In the Slovak population, we previously identified significant positive associations between PV and DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1 *14:04, DRB1*14:05, DQB1*03:02, and DQB1*05:03.8 Thus, the purpose of this study was to examine the International Journal of Dermatology 2014
1
2
Report
Svecova et al.
HLA alleles and disease severity in pemphigus
relationship between HLA class II alleles associated with PV and variations in the phenotype of PV. Materials and methods The study was performed in the Bullous Disorder Unit in the Department of Dermatovenereology, University Hospital of Comenius University in Bratislava, Slovakia, in cooperation with the Institute of Immunology, Faculty of Medicine, Comenius University. Forty-four unrelated Caucasian PV patients from various parts of Slovakia were investigated. This study was designed to uncover any association between HLA class II alleles and the severity of PV in Slovak patients. The PV patients were diagnosed based on clinical, histopathological, and direct immunofluorescence findings before enrollment in the study. HLA class II alleles were typed by polymerase chain reaction with sequence-specific primers (PCR-SSP) from our previous study. Commercially available primer kits (Olerup SSP DQ-DR Combi Tray; Olerup SSP AB,
Statistical analysis Data were compiled electronically using Excel and analyzed using IBM SPSS Statistics Version 20 (IBM Corp., Armonk, NY, USA). We used frequency tables for the statistical analysis of numerical variables, including the mean, median, confidence intervals (CIs), standard deviation (SD), minimum, maximum, and range. The different variables were calculated with 95% CIs. Normal distributions of the numerical data were obtained using the mean values and SDs. Numerical data with non-normal distributions were evaluated using the non-parametric Mann–Whitney U test for comparisons between two datasets, and the Kruskal–Wallis test was used for comparisons among more than two datasets. Associations between the categorized variables and outcomes were assessed using Fisher’s exact test. Statistical significance was defined by a P-value of 10 years had significantly higher anti-DsG3 IgG4 autoantibody levels than patients with a recent onset of disease within the past two years. These results remained significant only in patients with active disease and not in remittent patients. Additionally, in the same study, antiDsg3 IgG4 autoantibody levels were significantly higher in patients who carried one or both of the disease-associated HLA alleles (DRB1*04:02 and DQB1*05:03) than in carriers of other HLA alleles.15 In our previous study, we uncovered correlations between DRB1* and DQB1* alleles and clinical phenotypic variables in PV patients. Analysis of the DRB1* and DQB1* alleles with additional clinical parameters highlights the association of International Journal of Dermatology 2014
DRB1*04:02 alleles with severe PV (P = 0.031) and with the mucocutaneous type of PV (P = 0.024); further, the frequency of the alleles is greater than in carriers of other HLA alleles. Moreover, we documented an association of DQB1*03:02 alleles in patients with severe PV (P = 0.031) and in female patients (P = 0.016). These results are in concordance with our previous study, in which we documented more severe disease in female than in male PV patients. Simultaneously, we recorded a longer remission survival time in female PV patients compared with male PV patients.16 Furthermore, the presence of the DQB1*03:02 allele has been shown to be increased significantly in PV patients.6,11,14,17 Limited data indicate an association of DRB1*14:54 with PV, perhaps because this allele was included in DRB1*14:01 until 2005,18 although an association between DRB1*14:54 and PV patients has been reported.14 Likewise, we previously found an association of DRB1*14:54 and PV in PV patients.8 In the current ª 2014 The International Society of Dermatology
Svecova et al.
study, we found an association between DRB1*14:54 and PV only in our male patients (P = 0.047). We cannot, however, explain this association of DRB1*14:54 with gender. Moreover, the distribution of DRB1*14:54 was similar with regard to other evaluated clinical parameters and did not significantly differ between any other groups. Specific HLA-DR and HLA-DQ molecules may influence susceptibility or resistance to PV, and thus these alleles may, perhaps, contribute to the variability in clinical phenotypes in PV patients. We believe that DBR1* and DQB1* alleles may play a role in the pathogenesis and course of the disease. Likewise, these alleles may influence additional factors that contribute to the clinical heterogeneity of PV, including the heterogeneous susceptibility to various immunosuppressive drugs and the unpredictable disease course observed in PV patients. Several triggers, including infection, pregnancy, drug intake, diet, and sun exposure, are thought to evoke pemphigus.1 Furthermore, stress may influence the course of autoimmune disease,19 and stress was found to worsen the course of PV during local armed conflict in Macedonia.20 Despite this knowledge, the course of PV remains unpredictable; thus, the identification of factors that contribute to the course of the disease and its prognosis is highly desirable. In our recent study, we reported the finding of a poor prognosis in patients with multiple mucosal lesions, severe disease, and longer remission survival time, which was more frequently found in females than in males.16 Other authors have documented poor prognoses in PV patients aged ≤40 years with initial mucosal involvement.21 Finally, first relapse-free survival in PV with mucosal involvement was found to be a predictor of poor prognosis.22 HLA polymorphisms may provide genetic support for the variability in PV outcomes. Our previous study suggests that certain gene polymorphisms of various cytokines, including tumor necrosis factor-a and interleukin-10, may influence genetic susceptibility to PV and may contribute to the phenotypic variability of the disease.23 In concordance with previously reported studies,3,24 we found that 11.4% of first-degree relatives of PV patients suffered from autoimmune disease, including type 1 diabetes mellitus, rheumatoid arthritis, and thyroidal autoimmunity. The frequency of autoimmune disease is considered to be 5–7% in the general population.25 Multiple autoimmune disorders suggest that various conditions result from an abnormality in immune regulation and thus that clinically distinct autoimmune phenotypes may represent pleiotropic outcomes of a genetic trait, the manifestation of which may depend on complex interactions between genes and the environment.26 In concordance with these observations, 22.7% of PV patients in the present series had additional autoimmune disease, including thyroidal autoimmunity, rheumatoid arthritis, ulcerative colitis, vitiª 2014 The International Society of Dermatology
HLA alleles and disease severity in pemphigus
Report
ligo, and psoriasis. By contrast, another study found only 6.3% of PV patients documented concurrent autoimmune diseases, including autoimmune thyroid disease and rheumatoid arthritis, and 2.6% of first-degree relatives had autoimmune diseases.27 One limitation of the present study stems from its relatively small number of participants, which is attributable to the rarity of the disease. We appreciate the new ABSIS system, which provides a precise definition of the disease phenotype and allows for the comparison of results across various studies. Our results suggest that the HLA DRB1* and DQB1* alleles not only influence susceptibility to PV but may also contribute to the variable clinical phenotype of PV. Moreover, our studies indicate that genetic background may contribute to the outcome of the disease, including its unpredictable course and variability in treatment efficacy, because some of the alleles were present at significantly higher frequencies in patients with severe disease, who frequently experience these problems. In addition, in the present series, the mucocutaneous type of PV was found more frequently in patients with severe PV than in those with mild PV, and females exhibited severe disease more frequently than men. Conclusions Specific HLA DRB1*and DQB1* alleles may influence susceptibility to PV and, moreover, may contribute to the phenotypic variability of PV. We found DRB1*04:02 and DQB1*03:02 to be associated with severe PV. In addition, we identified a correlation between DRB1*04:02 and the mucocutaneous type of PV, and a correlation between the DQB1*03:02 allele and female gender. Moreover, our studies indicate that genetic background may contribute to the outcome of the disease, including its unpredictable course and variability in treatment efficacy, because some of the alleles were present at significantly higher frequencies in patients with severe disease. Other PV-associated DRB1* and DQB1* alleles, including DRB1*04, DRB1*14, and DQB1*05, were distributed without significant differences within all evaluated phenotypes of PV. Acknowledgments The authors thank Professor Jagienka Jautova, MD, PhD (Department of Dermatovenereology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia) and Eva Vrtikova, MD (Department of Dermatovenereology, Faculty of Medicine, Slovak Medical University, Nitra, Slovakia) for their cooperation, and BioMed Proofreading LLC (Cleveland, OH, USA) for Englishlanguage editing. International Journal of Dermatology 2014
5
6
Report
Svecova et al.
HLA alleles and disease severity in pemphigus
References 1 Svecova D. Pemphigus Bratislava: Bonus 2009: 23–46. 2 Meyer N, Misery L. Geoepidemiologic considerations of autoimmune pemphigus. Autoimmun Rev 2010; 9: 379–382. 3 Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 25: 1094–1108. 4 Kricheli D, David M, Frusic-Zlotkin M, et al. The distribution of pemphigus vulgaris-IgG subclasses and their reactivity with desmoglein 3 and 1 in pemphigus patients and their first-degree relatives. Br J Dermatol 2000; 143: 337–342. 5 Brandsen R, Frusic-Zlotkin M, Lyubimov H, et al. Circulating pemphigus IgG in families of patients with pemphigus: comparison of indirect immunofluorescence, direct immunofluorescence, and immunoblotting. J Am Acad Dermatol 1997; 36: 44–52. 6 Lee E, Lendas KA, Chow S, et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Hum Immunol 2006; 67: 125–139. 7 Yan L, Wang JM, Zeng K. Association between HLA-DRB1 polymorphisms and pemphigus vulgaris: a meta-analysis. Br J Dermatol 2012; 167: 768–777. 8 Parnicka Z, Svecov a D, Javor J, et al. High susceptibility to pemphigus vulgaris due to HLA-DRB1*14:54 in the Slovak population. Int J Dermatol 2013; 40: 471–475. 9 Sebaratnam D, Murrel D. Objective scoring system for disease activity in autoimmune bullous diseases. Dermatol Clin 2011; 29: 515–520. 10 Werth VP. Measuring extent and activity of disease in pemphigus. SYM-SO36, Educational Sessions Handouts, 69th Annual meeting of the American Academy of Dermatology, February 4–8, 2011, New Orleans, LA. 11 Carcassi C, Cottoni F, Floris L, et al. HLA haplotypes and class II molecular alleles in Sardinian and Italian patients with pemphigus vulgaris. Tissue Antigens 1996; 6: 662–667. 12 Loiseau P, Lecleach L, Prost C. HLA class II polymorphism contributes to specify desmoglein derived peptides in pemphigus vulgaris and pemphigus foliaceus. J Autoimmun 2000; 15: 67–73. 13 Gonzalez-Escribano MF, Jimenez G, Walter K. Distribution of HLA class alleles among Spanish patients with pemphigus vulgaris. Tissue Antigens 1998; 52: 275–278. 14 Saha M, Harman K, Mortimer NJ, et al. Pemphigus vulgaris in white Europeans is linked with HLA class II
International Journal of Dermatology 2014
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16
17
18
19 20
21
22
23
24
25
26
27
allele HLA DRB*1454 but not DRB1*1401. J Invest Dermatol 2010; 130: 311–314. Dhandha MM, Seiffert-Sinha K, Sinha AA. Specific immunoglobulin isotypes correlate with disease activity, morphology, duration and HLA association in pemphigus vulgaris. Autoimmunity 2012; 45: 516–526. Svecova D. Pemphigus vulgaris: a clinical study of 44 cases over a 20-year period. Int J Dermatol 2013; 2014, In press. Shams S, Amirzargar AA, Yousefi M, et al. HLA class II (DRB, DQA1 and DQB1) allele and haplotype frequencies in the patients with pemphigus vulgaris. J Clin Immunol 2009; 29: 175–179. Marsh SGE, Albert ED, Bontrop RE, et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010; 75: 291–455. Stojanovich L. Stress and autoimmunity. Autoimmun Rev 2010; 9: 271–276. VIckova-Laskoska MT, Laskoski DS, Kamberova S, et al. Epidemiology of pemphigus in Macedonia: a 15-year retrospective study (1990–2004). Int J Dermatol 2007; 46: 253–258. Minouni D, Bar H, Gdalevich M, et al. Pemphigus, analysis of 155 patients. J Eur Acad Dermatol Venereol 2010; 24: 947–952. Khaled A, Taazayet SBBen Alaya N, et al. The course and prognosis of pemphigus in 47 Tunisian patients. J Eur Acad Dermatol Venereol 2013; 27: 81–85. Javor J, Chmurova N, Parnicka Z, et al. TNF-alpha and IL-10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population. J Eur Acad Dermatol Venereol 2010; 24: 65–68. Jacobson DL, Ganges SJ, Rose NR, et al. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–243. Buc M. Immunogenetic mechanisms in autoimmune process: disorders of immune regulatory mechanisms, genetic determination of autoimmunity, effector mechanisms of autoimmune processes and their therapy. Bratisl Lek Listy 1996; 97: 660–668. Prahalad S, Shear ES, Thompson SD, et al. Increased prevalence of familial autoimmunity in simplex and multiplex families with juvenile rheumatoid arthritis. Arthritis Rheum 2002; 46: 1851–1856. Leshem YA, Katzenelson V, Yosipovitch G, et al. Autoimmune disease in patients with pemphigus and their first-degree relatives. Int J Dermatol 2011; 50: 827–831.
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