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Incidence and prevalence of systemic sclerosis in Campo Grande, State of Mato Grosso do Sul, Brazil

Abstract

Introduction:

Systemic sclerosis is an autoimmune disease which shows extreme heterogeneity in its clinical presentation and that follows a variable and unpredictable course. Although some discrepancies in the incidence and prevalence rates between geographical regions may reflect methodological differences in the definition and verification of cases, they may also reflect true local differences.

Objectives:

To determine the prevalence and incidence of systemic sclerosis in the city of Campo Grande, state capital of Mato Grosso do Sul (MS), Brazil, during the period from January to December 2014.

Methods:

All health care services of the city of Campo Grande – MS with attending in the specialty of Rheumatology were invited to participate in the study through a standardized form of clinical and socio-demographic assessment. Physicians of any specialty could report a suspected case of systemic sclerosis, but necessarily the definitive diagnosis should be established by a rheumatologist, in order to warrant the standardization of diagnostic criteria and exclusion of other diseases resembling systemic sclerosis. At the end of the study, 15 rheumatologists reported that they attended patients with systemic sclerosis and sent the completed forms containing epidemiological data of patients.

Results:

The incidence rate of systemic sclerosis in Campo Grande for the year 2014 was 11.9 per million inhabitants and the prevalence rate was 105.6 per million inhabitants. Systemic sclerosis patients were mostly women, white, with a mean age of 50.58 years, showing the limited form of the disease with a mean duration of the disease of 8.19 years. Regarding laboratory tests, 94.4% were positive for antinuclear antibody, 41.6% for anti-centromere antibody and 19.1% for anti-Scl70; anti-RNA Polymerase III was performed in 37 patients, with 16.2% positive.

Conclusions:

The city of Campo Grande, the state capital of MS, presented a lower incidence/prevalence of systemic sclerosis in comparison with those numbers found in US studies and close to European studies’ data.

Keywords:
Systemic sclerosis; Scleroderma; Incidence; Prevalence; Brazil

Resumo

Introdução:

A esclerose sistêmica (ES) é uma enfermidade autoimune, extremamente heterogênea na sua apresentação clínica e segue um curso variável e imprevisível. Embora algumas discrepâncias nas taxas de incidência e prevalência entre regiões possam refletir as diferenças metodológicas na definição e verificação dos casos, elas também podem refletir as verdadeiras diferenças locais.

Objetivos:

Conhecer a prevalência e incidência da ES na cidade de Campo Grande, capital do Estado de Mato Grosso do Sul (MS), Brasil, de janeiro a dezembro de 2014.

Métodos:

Todos os serviços de saúde de Campo Grande (MS) que tinham atendimentos na especialidade de reumatologia foram convidados a participar do estudo por meio de ficha padronizada de avaliação clínica e sociodemográfica. Médicos de qualquer especialidade poderiam reportar um caso suspeito de ES, mas obrigatoriamente o diagnóstico definitivo deveria ser feito por um reumatologista, para garantir a padronização dos critérios diagnósticos e excluir outras doenças que se assemelham à ES. No fim do estudo 15 reumatologistas relataram ter atendido pacientes com diagnóstico de ES e enviaram os formulários preenchidos com os dados epidemiológicos dos pacientes.

Resultados:

A taxa de incidência de ES em Campo Grande em 2014 foi de 11,9 por milhão/habitantes e a de prevalência foi de 105,6 por milhão/habitantes. Os pacientes com ES eram principalmente mulheres, da cor branca, média de 50,58 anos, forma limitada da doença e tempo de evolução médio da doença de 8,19 anos. Em relação aos exames laboratoriais, observou-se a positividade de 94,4% para o ANA, 41,6% para ACA e 19,1% para anti-Scl70, o anticorpo anti-POL3 foi feito em apenas 37 pacientes, com positividade de 16,2%.

Conclusões:

A capital do Estado de Mato Grosso do Sul, Campo Grande, apresentou dados de incidência e prevalência de ES inferiores aos encontrados em estudos americanos e próximos aos dados observados em estudos europeus.

Palavras-chave
Esclerose sistêmica; Esclerodermia; Incidência; Prevalência; Brasil

Introduction

Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue, extremely heterogeneous in its clinical presentation, with the involvement of multiple systems and that follows a varied and unpredictable course.11 Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557-67. Its etiology remains unknown; a multifactorial cause was suggested, possibly triggered by environmental factors in a genetically predisposed individual.22 Herrick AL, Worthington J. Genetic epidemiology systemic sclerosis. Arthritis Res. 2002;4:165-8.

The classification of SSc patients takes into account the extension of skin involvement and the presence of overlapping with certain characteristics of other autoimmune rheumatic diseases.33 Vilas AP, Veiga MZ, Abecasis P. Esclerose sistémica – perspectivas actuais. Med Int. 2002;9:111-20.

4 Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol. 2005;26:596-602.
-55 Kayser C, Andrade LEC. Esclerose sistêmica. In: Sato E, editor. Guias de medicina ambulatorial e hospitalar – reumatologia. São Paulo: Manole; 2004. p. 111–20.

In the United States, the reported prevalence rate for SSc was 1–5 per 1000 inhabitants. Two prevalence studies conducted in England found a similar value, about 1 per 1000 inhabitants.44 Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol. 2005;26:596-602. Regarding the incidence of SSc, an annual rate of 0.6–19 new cases per million inhabitants was estimated.55 Kayser C, Andrade LEC. Esclerose sistêmica. In: Sato E, editor. Guias de medicina ambulatorial e hospitalar – reumatologia. São Paulo: Manole; 2004. p. 111–20. Steen et al. found an incidence rate of SSc in 3.8–13.9 new cases per million inhabitants per year.33 Vilas AP, Veiga MZ, Abecasis P. Esclerose sistémica – perspectivas actuais. Med Int. 2002;9:111-20. A study in a southern state in Australia reported an annual incidence of 22.8 new cases of SSc per million inhabitants and a prevalence of 233 cases per million inhabitants in 1999, with values similar to those in American studies conducted in the same period.66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.

More recently, a systematic review study reported similar prevalences of SSc observed in the UK and Japan, with 31 and 38 cases per million inhabitants, respectively.77 Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165-70. It is noteworthy that, in addition to regional genetic variations, environmental exposures can also have an effect on the prevalence and incidence rates. For example, silica exposure appears to increase the risk of developing SSc; however, this triggering action is only important to a small proportion of male patients.77 Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165-70.

Interestingly, there has been an increase in SSc incidence rates in different geographical regions,66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.,88 Furst DE, Fernandes AW, Iorga SR, Greth W, Bancroft T. Epidemiology of systemic sclerosis in a large US managed care population. J Rheumatol. 2012;39:784-6. possibly due to an earlier diagnosis and also to the use of new classification criteria. For example, in the United States, the rate for new cases increased from 0.6 cases per million in 1947 in Tennessee to 19.0 cases per million in 1991 in the Detroit area.99 Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223-35. Likewise, the prevalence and incidence of SSc appear to be larger in populations of European ancestry, and lower in groups of Asian descent.77 Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165-70. In Taiwan, the incidence and prevalence rates were 10.9 and 56.3 cases per million cases/inhabitants, respectively.1010 Kuo CF, See LC, Yu KH, Chou IJ, Tseng WY, Chang HC, et al. Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan. Scan J Rheumatol. 2011;40:373-8.

In epidemiology studies of SSc, different results are observed in different regions of the world, and this also occurs in one same country or city.66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.88 Furst DE, Fernandes AW, Iorga SR, Greth W, Bancroft T. Epidemiology of systemic sclerosis in a large US managed care population. J Rheumatol. 2012;39:784-6.,1010 Kuo CF, See LC, Yu KH, Chou IJ, Tseng WY, Chang HC, et al. Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan. Scan J Rheumatol. 2011;40:373-8. SSc prevalence data in a multi-ethnic French district suggested that the disease appears to be more frequent and severe in a population of non-European origin, which speaks in favor of the idea that the race could influence the susceptibility to the development of SSc, and also the clinical profile.1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37. In this same line, the European group of SSc research pointed out that geographical variations in patients with SSc may also have an influence with regard to antibody associations and in the rate of occurrence among women and men, but no associations between races were found.1212 Walker UA, Tyndall A, Czirják L, Denton CP, Farge-Bancel D, Kowal-Bielecka O, et al. Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis. 2009;68:856-62.

There are no published data on the prevalence and incidence of SSc in the Brazilian population, since this is a rare condition. Thus, due to the scarcity of national studies and the high degree of miscegenation found in the Brazilian population1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81. we aimed to study the prevalence and incidence of systemic sclerosis in the city of Campo Grande, the state capital of Mato Grosso do Sul, Brazil, during the period from January to December 2014.

Objectives

To determine the prevalence and incidence of systemic sclerosis in the city of Campo Grande, Mato Grosso do Sul, Brazil, during the period from January to December 2014.

Methods

All health care services in Campo Grande – MS with Rheumatology specialty participated in this prospective observational study.

The Rheumatology units in the city are distributed among the Medical School Teaching Hospital of the Universidade Federal de Mato Grosso do Sul, the Regional Hospital of Mato Grosso do Sul, Santa Casa de Campo Grande, the outpatient clinic of the Medical Specialties Center of the Municipality of Campo Grande, outpatient clinics of the Medical Specialties Center of Anhanguera-Uniderp Medicine School, outpatient clinics of the Caixa de Assistência dos Servidores de Mato Grosso do Sul, and several private Rheumatology clinics.

Prior to starting this study, all rheumatologists were informed by e-mail and phone call about the procedures for data collection and objectives of this research. Periodically, we asked (by e-mail or phone call) to all involved doctors to complete a standardized form for collecting demographic and laboratory data of all patients diagnosed with systemic sclerosis and evaluated during the study period, regardless of whether they were new or old cases. Any doctor could report a suspected case of SSc (general practitioner, dermatologist, vascular surgeon, gastroenterologist, pulmonologist, etc.), but the definitive diagnosis necessarily should be established by a rheumatologist, in order to ensure the standardization of diagnostic criteria and to rule out other diseases resembling SSc, for example, mixed connective tissue disease (MCTD).

At the end of the study, 15 rheumatologists reported patients with SSc, and sent the completed forms with epidemiological data of their patients; verbal or written consent from all patients was requested. The reasons for other MS rheumatologists did not report cases were: they did not examine patients with SSc in the period, or the patients seen did not live in Campo Grande – MS or the patients had already been reported by another colleague (patient's duplicity). To avoid data redundancy in the event that an individual patient had been assessed by more than a rheumatologist, these patients were identified by the initials of their names and their date of birth.

Patients diagnosed with SSc and non-residents of Campo Grande – MS were not considered for incidence and prevalence estimates.

To be selected, patients with SSc should meet the following criteria:

  • - Meet the 2013 classification criteria of the ACR/EULAR for SSc1414 Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rhematology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72:1747-55.;

  • - In the case of absence of skin thickening, patients should meet the 2001 criteria of LeRoy and Medsger for early SSc.1515 LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28:1573-6.

State of origin, provenance, age, gender and race/color data, and time elapsed from first symptoms to diagnosis, disease duration, and clinical form of SSc were collected, and laboratory tests such as antinuclear antibody (ANA) anti-DNA topoisomerase I antibody (anti Scl70), anticentromere antibody (ACA) and anti-RNA polymerase III (anti-RNAP III) also were conducted.

The methods used in autoantibody survey were, respectively:

  1. Antinuclear antibodies (ANA) survey

    Immunofluorescent antibody test for ANA, with HEp2 cells as a substrate (Faar technique), according to the II Brazilian Consensus on Antinuclear Factor in Hep-2 cells (2003) criteria1616 Dellavance A, Gabriel A, Cintra AFU, Ximenes AC, Nuccitelli B, Tabilerti BH, et al. II Consenso Brasileiro de Fator Antinuclear em células Hep-2. Rev Bras Reumatol. 2003;43:129-40. for the interpretation of results.

    Sera were considered positive with a titer ≥1/160, with dilution a negative fluorescence.

  2. Anticentromere survey – Indirect immunofluorescence technique with HEp2 cells as a substrate, according to the II Brazilian Consensus on Antinuclear Factor in Hep-2 cells (2003) criteria1616 Dellavance A, Gabriel A, Cintra AFU, Ximenes AC, Nuccitelli B, Tabilerti BH, et al. II Consenso Brasileiro de Fator Antinuclear em células Hep-2. Rev Bras Reumatol. 2003;43:129-40. for the interpretation of results.

  3. Anti-DNA topoisomerase I (anti Scl70) survey – Immunoassay technique1717 Hildebrandt S, Weiner ES, Senecal JL, Noell GS, Earnshaw WC, Rothfielda NF. Autoantibodies to topoisomerase I (Scl-70): analysis by gel diffusion, immunoblot, and enzyme-linked immunosorbent assay. Clin Immunol Immunop. 1990;57:399-410.; the sample was considered nonreactive with values <20 units, weakly reactive between 20 and 39 units, moderately reactive between 40 and 80 units and strongly reactive (higher values) with values >80 units.

  4. Anti-RNA polymerase III Antibody survey – ELISA technique1818 Codullo V, Morozzi G, Bardoni A, Salvini R, Deleonardi G, Pità O, et al. Validation of a new immunoenzymatic method to detect antibodies to RNA polymerase III in systemic sclerosis. Clin Exp Rheumatol. 2007;25:373-7.; the sample was considered negative with values <20 units, weakly reactive between 20 and 39 units, moderately reactive between 40 and 80 units, and strongly reactive (higher values) with >80 units.

Statistical analysis

IBGE data1919 Estimativas da população residente no Brasil e unidades da federação com data de referência em 1º de julho de 2014. Rio de Janeiro: IBGE; 2014. Diretoria de Pesquisas (DPE), Coordenação de População e Indicadores Sociais (Copis) (doi. http://www.ibge.gov.br/home/presidencia/noticias/pdf/analise_estimativas_2014.pdf estimativas2014.pdf).
http://www.ibge.gov.br/home/presidencia/...
with estimates of the resident population in Brazil and in Units of the Federation and with a reference date of July 1, 2014, were considered for the calculation of the incidence and prevalence of SSc.

Data is presented in absolute and relative frequencies, means and standard deviations, and with a confidence interval of 95% and statistically significant values for p < 0.05.

Results

During 2014, a total of 166 patients with scleroderma or systemic sclerosis were treated in various outpatient clinics and Rheumatology Units in the city of Campo Grande – MS. Eighty-nine patients who lived in the city had a definitive diagnosis of systemic sclerosis and were clinically examined in that city during the study period.

Of this total, 10 were new cases of SSc diagnosed during the year 2014 and 79 patients had already been previously diagnosed. Therefore, the incidence rate of SSc in the city of Campo Grande – MS during the year 2014 was 11.9 per million inhabitants and the prevalence rate was 105.6 per million inhabitants. The data are presented in Table 1, which also lists comparisons with incidence and prevalence rates in other countries and regions.

Table 1
Comparison of incidence and prevalence rates of patients with systemic sclerosis (SSc) in several geographical regions.

Results observed in systemic sclerosis

Among the 89 patients with SSc, 86 were women (96.6%) and 3 were men (3.4%) with a mean age of 50.58 ± 13.85 years (mean ± standard deviation).

Thirty-one patients (34.8%) with SSc were born in the city of Campo Grande; 31 patients (34.8%) were born in the countryside of MT, and 27 patients (30.4%) were born in other states.

Of the 89 patients with SSc, 58 patients (65.2%) reported being white, 20 patients (22.4%) had a brown color, 8 patients (9.0%) were black and 3 patients yellow (3.4%).

Regarding clinical forms of SSc, 38 patients (42.7%) showed the limited form, 24 patients (27.0%) exhibited the diffuse form, 17 patients (19.1%) show overlapping with other collagen diseases, 6 patients (6.7%) exhibited the sine scleroderma form and 4 patients (4.5%) had the early form. Among the 17 patients with the overlapped form, 8 patients (47.1%) concomitantly had systemic lupus erythematosus, 5 patients (29.4%) had rheumatoid arthritis, and 4 patients (23.5%) had their SSc associated with inflammatory myopathies.

Patients with SSc were already presenting symptoms for 4.74 ± 5.01 years before their diagnosis, and the disease duration, in general, was about 8.19 ± 7.40 years.

ANA was positive in 84 patients with SSc (94.4%), and the main patterns found in these patients were: fine speckled nuclear pattern (30 patients – 36.6%), centromeric pattern (29 patients – 35.4%) and quasi-homogeneous nuclear pattern, with metaphase plate staining for 5–10 points (12 patients – 14.6%). Among all patients, 37 (41.6%) had positive ACA, 17 (19.1%) were positive for anti-Scl70 and 1 patient (1.1%) was simultaneously positive for both autoantibodies. On the other hand, the anti-RNAP III was performed in only 37 patients, being positive in 6 of these (16.22%).

The characteristics of the epidemiological profile of patients with SSc and the results observed in laboratory tests for autoantibodies of the same patients are shown respectively in Tables 2 and 3.

Table 2
Distribution of patients evaluated in this study and results of epidemiological data in patients with systemic sclerosis (SSc).
Table 3
Results of autoantibodies in patients with systemic sclerosis (SSc).

Discussion

In this study, an unprecedented and representative sample of the Midwest of Brazil was defined, having been characterized by a heterogeneous group of patients with various spectra of disease and different stages of clinical manifestations and activities of the disease, but that is very similar to what occurs in other populations of patients in this country and even from other locations.33 Vilas AP, Veiga MZ, Abecasis P. Esclerose sistémica – perspectivas actuais. Med Int. 2002;9:111-20.,1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24.2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.

A systematic review of 32 articles published from 1969 to 2006 indicated that the incidence rate for SSc varied from 0.6 to 122 cases per million inhabitants; on the other hand, the prevalence rate for the same disease ranged from 7 to 489 cases per million inhabitants,99 Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223-35. which is consistent with the rates observed in our study. Several geographical variations were observed, with a higher prevalence of SSc in the United States (276 cases per million inhabitants) and Australia (233 cases per million inhabitants) versus Japan and Europe, where one still observed a north–south variable gradient, with lower prevalence rates in northern European countries.99 Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223-35.,1212 Walker UA, Tyndall A, Czirják L, Denton CP, Farge-Bancel D, Kowal-Bielecka O, et al. Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis. 2009;68:856-62.

The rates found for SSc in our study (incidence of 11.9 per million inhabitants and prevalence of 105.6 per million inhabitants) are more similar to those for European countries. For example, the prevalence of SSc in a French multi-ethnic district was 158.3 cases per million inhabitants in 20011111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.; in the north of England a prevalence of 88.0 cases per million inhabitants in 2000 was found.2424 Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology. 2004;43:596-602. A peculiarity of the city of Campo Grande – MS is that its population was mainly composed of national immigrants and foreigners, who came mainly from the states of Minas Gerais, Rio Grande do Sul, Parana, and Sao Paulo, and from countries like Germany, Spain, Italy, Japan, Paraguay, Portugal, Syria and Lebanon.2525 Revista de divulgação do arquivo histórico de Campo Grande – MS (ARCA) n°13/2007. Tema: Campo Grande–30 anos de capital. O olhar da história e a perspectiva do futuro. Available at: http://www.capital.ms.gov.br/arca/canaisTexto?id_can=7304.
http://www.capital.ms.gov.br/arca/canais...

There are no Brazilian studies published on the incidence or prevalence of SSc. In South America, the incidence and prevalence of SSc observed in Buenos Aires – Argentina were 21.2 cases and 296 cases per million inhabitants, respectively.2626 Rosa JE, Soriano ER, Narvaez-Ponce L, del Cid CC, Imamura PM, Catoggio LJ. Incidence and prevalence of systemic sclerosis in a healthcare plan in Buenos Aires. J Clin Rheumatol. 2011;17:59-63. In the Caribbean, a lower incidence was observed, with a total of 17 cases of SSc observed in the Afro-descendant population of Barbados during an observation period of 10 years (1996–2006).2727 Flower C, Nwankwo C. Systemic sclerosis in an Afro-Caribbean population. A review of demographic and clinical features. West Indian Med J. 2008;57:118-21. In North America, the incidence and prevalence of SSc observed in the United States were higher, respectively 19.3 and 242.0 cases per million inhabitants.2828 Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246-55.

Although some discrepancies in the incidence and prevalence of SSc between regions may reflect methodological differences in the definition and verification of cases, they can also reflect true local differences. These regional differences could occur due to the diverse genetic susceptibility to the development of SSc, or to different degrees of exposure to environmental factors incriminated in the pathogenesis.66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.

In Brazil, as in all regions of the world, there were some differences in the rate of women affected by SSc compared to men, and female predominance has been observed in all studies.66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.,77 Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165-70.,1010 Kuo CF, See LC, Yu KH, Chou IJ, Tseng WY, Chang HC, et al. Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan. Scan J Rheumatol. 2011;40:373-8.,1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.,1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24.,2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.,2626 Rosa JE, Soriano ER, Narvaez-Ponce L, del Cid CC, Imamura PM, Catoggio LJ. Incidence and prevalence of systemic sclerosis in a healthcare plan in Buenos Aires. J Clin Rheumatol. 2011;17:59-63.3838 Jezler SFO, Santiago MB, Andrade TL, Araujo Neto C, Braga H, Cruz AA. Comprometimento do interstício pulmonar em portadores de esclerose sistêmica progressiva. Estudo de uma série de 58 casos. J Bras Pneumol. 2005;31:300-6. While there is an agreement between the results of our study and those in the literature, a high female/male ratio of 28.6:1 in SSc was observed. For example, national data for SSc inform a variable rate of 7.7–32 women for every affected man1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,1818 Codullo V, Morozzi G, Bardoni A, Salvini R, Deleonardi G, Pità O, et al. Validation of a new immunoenzymatic method to detect antibodies to RNA polymerase III in systemic sclerosis. Clin Exp Rheumatol. 2007;25:373-7.,2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.,3737 Lo Monaco A, Bruschi M, La Corte R, Volpinari S, Trotta F. Epidemiology of systemic sclerosis in a district of northern Italy. Clin Exp Rheumatol. 2011;29(S65):S10-4.; in South America (Argentina), the rate is 17:12626 Rosa JE, Soriano ER, Narvaez-Ponce L, del Cid CC, Imamura PM, Catoggio LJ. Incidence and prevalence of systemic sclerosis in a healthcare plan in Buenos Aires. J Clin Rheumatol. 2011;17:59-63.; in Caribbean countries (Barbados and Puerto Rico), the rates are respectively 26:12727 Flower C, Nwankwo C. Systemic sclerosis in an Afro-Caribbean population. A review of demographic and clinical features. West Indian Med J. 2008;57:118-21. and 23:13333 Ríos G, Mayor AM. Clinical and sociodemographic features of Puerto Ricans with systemic sclerosis. Ethn Dis. 2010;20(S1):S185-9.; in North America (US and Canada), the rates are respectively 6.1:188 Furst DE, Fernandes AW, Iorga SR, Greth W, Bancroft T. Epidemiology of systemic sclerosis in a large US managed care population. J Rheumatol. 2012;39:784-6. and 7.6:13434 Bassel M, Hudson M, Taillefer SS, Schieir O, Baron M, Thombs BD. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology. 2011;50:762-7.; in Asia (Taiwan and Japan), the rates are respectively 3.5:11010 Kuo CF, See LC, Yu KH, Chou IJ, Tseng WY, Chang HC, et al. Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan. Scan J Rheumatol. 2011;40:373-8. and 14:13535 Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res. 1991;283:366-71.; in the Middle East (Iraq), the rate is 8.3:13636 Al-Adhadh RN, Al-Sayed TA. Clinical features of systemic sclerosis. Saudi Med J. 2001;22:333-6.; and in Europe (Italy, Germany, France and England), the rates are respectively 9.7:1,3737 Lo Monaco A, Bruschi M, La Corte R, Volpinari S, Trotta F. Epidemiology of systemic sclerosis in a district of northern Italy. Clin Exp Rheumatol. 2011;29(S65):S10-4. 5:1,2121 Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, et al. The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology. 2008;47:1185-92. 11.5:1,1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37. and 5.2:1.2424 Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology. 2004;43:596-602.

Regarding other demographic data found, the mean age of our patients with SSc (50.5 years) was almost consensus among the various studies in Brazil and overseas,66 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin N Am. 2003;29:239-54.,1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.,1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24.

21 Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, et al. The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology. 2008;47:1185-92.

22 Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1012 Italian patients. Medicine (Baltimore). 2002;81:139-53.

23 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.
-2424 Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology. 2004;43:596-602.,2828 Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246-55.

29 Alamanos Y, Tsifetaki N, Voulgari PV, Siozos C, Tsamandouraki K, Alexiou GA, et al. Epidemiology of systemic sclerosis in northwest Greece 1981-2002. Semin Arthritis Rheum. 2005;34:714-20.

30 Thomson PJR, Walker JG, Lu TY, Esterman A, Hakendorf P, Smith MD, et al. Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation. Intern Med J. 2006;36:489-97.
-3131 Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010;9:A311-8.,3333 Ríos G, Mayor AM. Clinical and sociodemographic features of Puerto Ricans with systemic sclerosis. Ethn Dis. 2010;20(S1):S185-9.,3434 Bassel M, Hudson M, Taillefer SS, Schieir O, Baron M, Thombs BD. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology. 2011;50:762-7.,3636 Al-Adhadh RN, Al-Sayed TA. Clinical features of systemic sclerosis. Saudi Med J. 2001;22:333-6.,3737 Lo Monaco A, Bruschi M, La Corte R, Volpinari S, Trotta F. Epidemiology of systemic sclerosis in a district of northern Italy. Clin Exp Rheumatol. 2011;29(S65):S10-4. with the diagnosis established between the fourth and fifth decades of life; only the African-Caribbean population2727 Flower C, Nwankwo C. Systemic sclerosis in an Afro-Caribbean population. A review of demographic and clinical features. West Indian Med J. 2008;57:118-21. had a younger mean age at diagnosis (37.3 years). With regard to the race informed by the patient, there was a prevalence of white color in our patients with SSc; however, one do not rules out the possibility of a bias of racial classification, due to the high degree of miscegenation found in the Brazilian population.1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81. In the South2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24. and Southeast2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8. of this country, there was a higher prevalence of white people with SSc. On the other hand, in the Northeast3838 Jezler SFO, Santiago MB, Andrade TL, Araujo Neto C, Braga H, Cruz AA. Comprometimento do interstício pulmonar em portadores de esclerose sistêmica progressiva. Estudo de uma série de 58 casos. J Bras Pneumol. 2005;31:300-6. region, a high prevalence of mulattoes and blacks was observed, probably because the study was conducted in a state with a known predominance of Afro-descendants (Bahia).

In this same vein, the European research group on SSc (EUSTAR) pointed out that geographical variations in patients with SSc may also have an impact with regard to antibody associations and in the rate of occurrence between women and men,1212 Walker UA, Tyndall A, Czirják L, Denton CP, Farge-Bancel D, Kowal-Bielecka O, et al. Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis. 2009;68:856-62. but this, as well as another study, found no association between races.1212 Walker UA, Tyndall A, Czirják L, Denton CP, Farge-Bancel D, Kowal-Bielecka O, et al. Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis. 2009;68:856-62.,3939 Nietert PJ, Mitchell HC, Bolster MB, Shaftman SR, Tilley BC, Silver RM. Racial variation in clinical and immunological manifestations of systemic sclerosis. J Rheumatol. 2006;33:263-8. In this study, most patients with SSc were born in the same state (73.4%), and the remaining patients were from different locations, but mainly from the states of São Paulo (13.44%) and Paraná (5.04%).

In this study, the limited clinical presentation of SSc showed a slight predominance of the diffuse form, in accordance with other descriptions in the country1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24.,2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.,3737 Lo Monaco A, Bruschi M, La Corte R, Volpinari S, Trotta F. Epidemiology of systemic sclerosis in a district of northern Italy. Clin Exp Rheumatol. 2011;29(S65):S10-4. and in most other populations.1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.,2121 Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, et al. The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology. 2008;47:1185-92.,2222 Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1012 Italian patients. Medicine (Baltimore). 2002;81:139-53.,2424 Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology. 2004;43:596-602.,2828 Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246-55.,3333 Ríos G, Mayor AM. Clinical and sociodemographic features of Puerto Ricans with systemic sclerosis. Ethn Dis. 2010;20(S1):S185-9.,3636 Al-Adhadh RN, Al-Sayed TA. Clinical features of systemic sclerosis. Saudi Med J. 2001;22:333-6. However, there are descriptions in which the diffuse form is more common in populations of Blacks vs. Caucasian populations,1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.,2828 Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246-55.,3838 Jezler SFO, Santiago MB, Andrade TL, Araujo Neto C, Braga H, Cruz AA. Comprometimento do interstício pulmonar em portadores de esclerose sistêmica progressiva. Estudo de uma série de 58 casos. J Bras Pneumol. 2005;31:300-6. including, in this case, those of African-Caribbean descent, in which a predominance of diffuse (63%) over the limited (37%) form was observed.2727 Flower C, Nwankwo C. Systemic sclerosis in an Afro-Caribbean population. A review of demographic and clinical features. West Indian Med J. 2008;57:118-21.

Regarding the laboratory tests performed in patients with SSc, antinuclear antibody (ANA) was present in 94.4% of patients – a similar result to most national studies1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24.,2323 Sampaio-Barros PD, Bortoluzzo AB, Marangoni RG, Rocha LF, Del Rio APT, Samara AM, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39:1971-8.,3737 Lo Monaco A, Bruschi M, La Corte R, Volpinari S, Trotta F. Epidemiology of systemic sclerosis in a district of northern Italy. Clin Exp Rheumatol. 2011;29(S65):S10-4. and in other regions.1111 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology. 2004;43:1129-37.,2121 Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, et al. The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology. 2008;47:1185-92.,2828 Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246-55.,3636 Al-Adhadh RN, Al-Sayed TA. Clinical features of systemic sclerosis. Saudi Med J. 2001;22:333-6.,4040 Hesselstrand R, Scheja A, Shen GQ, Wiik A, Åkesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology. 2003;42:534-40.4242 Bernstein RM, Steigerwald JC, Tan EM. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol. 1982;48:43-51. The main patterns observed were: fine speckled nuclear, centromeric, and quasi-homogeneous nuclear patterns. Bernstein et al. described ANA positivity in 97% of patients with SSc, mainly represented by fine speckled and centromeric patterns, besides the observation of an association with the nucleolar (speckled and homogenous) pattern in 33% of patients.4242 Bernstein RM, Steigerwald JC, Tan EM. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol. 1982;48:43-51. Hesselstrand et al. reported ANA positivity in 84% of patients with SSc, and the most observed patterns were: fine speckled (41%), homogeneous (25%), nucleolar (24%) and centromeric (18%) patterns.4040 Hesselstrand R, Scheja A, Shen GQ, Wiik A, Åkesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology. 2003;42:534-40.

Regarding specific antibodies for SSc observed in this study, anti-centromere (ACA), anti-DNA topoisomerase I (anti Scl70) and anti-RNA polymerase III (anti-RNAP III) positivity was observed in 41.6%, 19.1% and 16.2% of patients, respectively, and the percentages were comparable to those in two studies conducted in Southern Brazil,1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24. although Müller et al. had found surprisingly high levels of anti-RNAP III (41.18%).2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24. In this study, 60 of 89 patients (67.4%) were positive for at least one of those three specific autoantibodies to SSc (anti-Scl70, ACA, or anti-RNAP III).

The literature reports that the prevalence of highly specific autoantibodies associated with SSc or with overlap syndromes with SSC features is high in patients with SSc, primarily represented by ACA and anti Scl70,4040 Hesselstrand R, Scheja A, Shen GQ, Wiik A, Åkesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology. 2003;42:534-40.

41 Mierau R, Moinzadeh P, Riemekasten G, Melchers I, Meurer M, Reichenberger F, et al. Frequency of disease-associated and other nuclear autoantibodies in patients of the German network for systemic scleroderma: correlation with characteristic clinical features. Arthritis Res Ther. 2011;13:R172.
-4242 Bernstein RM, Steigerwald JC, Tan EM. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol. 1982;48:43-51. here including the Brazilian population with SSc.1313 Skare TL, Luciano AC, Fonseca AE, Azevedo PM. Autoanticorpos em esclerodermia e sua associação ao perfil clínico da doença. Estudo em 66 pacientes do sul do Brasil. An Bras Dermatol. 2011;86:1075-81.,2020 Müller CS, Paiva ES, Azevedo VF, Radominski SC, Lima Filho JHC. Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil. Rev Bras Reumatol. 2011;51:319-24. Although the studies report that the coexistence of these specific autoantibodies is rare in patients with SSc (1.6%),4040 Hesselstrand R, Scheja A, Shen GQ, Wiik A, Åkesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology. 2003;42:534-40.

41 Mierau R, Moinzadeh P, Riemekasten G, Melchers I, Meurer M, Reichenberger F, et al. Frequency of disease-associated and other nuclear autoantibodies in patients of the German network for systemic scleroderma: correlation with characteristic clinical features. Arthritis Res Ther. 2011;13:R172.
-4242 Bernstein RM, Steigerwald JC, Tan EM. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol. 1982;48:43-51. in this study, we observed two patients (2.2%) that were concomitantly positive for specific autoantibodies: one patient with the diffuse form presented concomitant positivity for anti Scl70 and ACA, and another patient also with the diffuse form had concomitant positivity for anti Scl70 and anti-RNAP III.

Our conclusion is that the city of Campo Grande, the state capital of Mato Grosso do Sul, presented lower incidence and prevalence of SSc versus those found in American studies and similar to those observed in European studies. This incidence, however, may still be underestimated, especially in patients with the limited form of SSc, because in these individuals only the Raynaud's phenomenon is apparent for many years, with little systemic involvement; thus, they may not seek medical attention. We suggest that epidemiological surveys in SSc are conducted in other Brazilian cities, in order to reflect possible regional differences and environmental influences in the development of both diseases.

Acknowledgements

We thank Dr. Natalino Yoshinari for his encouragement to this study and Dr. Albert Schiaveto de Souza for the statistical analysis.

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Publication Dates

  • Publication in this collection
    Mar-Apr 2017

History

  • Received
    12 Oct 2015
  • Accepted
    2 May 2016
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