Abstract

Rheumatoid arthritis (RA) is among the most prevalent chronic autoimmune and inflammatory diseases worldwide. The aim of this study was to establish a pooled estimate of the RA prevalence in South America by means of a meta-analysis of the available epidemiologic studies. Systematic searches in PubMed, Lilacs, SciELO, Scopus, and Web of Science databases (updated May 2019) were done followed by a systematic grey literature search to identify original research articles and reports, published after 2000, providing data of RA prevalence in any South American country. Proportion meta-analysis of weighted pooled was performed, with between-trial heterogeneity assessed by the inconsistency relative index. Sensitivity analyses and sub-group analyses were also done. A total of 25 articles, representing 27 population-based studies were included. Pooled prevalence of RA resulted in 0.48% with 591,981 cases in a population of 114,537,812 individuals (I2=99%). Brazil and Colombia presented the lowest rates of RA prevalence 0.22%, and 0.24%, respectively. RA prevalence in indigenous population was higher 1.45%, and studies using COPCORD method reported also the highest rates 1.07%.

Key words:
Arthritis Rheumatoid; Prevalence; Latin America; Health Services Accessibility; Meta-Analysis as Topic

Resumo

A artrite reumatóide (AR) está entre as doenças autoimunes e inflamatórias crônicas mais prevalentes no mundo. O objetivo deste estudo foi estabelecer uma estimativa conjunta da prevalência da AR na América do Sul por meio de uma meta-análise dos estudos epidemiológicos disponíveis. Buscas sistemáticas nas bases de dados PubMed, Lilacs, SciELO, Scopus e Web of Science (atualizado em maio de 2019) foram seguidas por uma busca sistemática na literatura cinzenta para identificar artigos e relatórios de pesquisa originais, publicados após 2000, fornecendo dados de prevalência de AR em qualquer país da América do Sul. Foi realizada uma meta-análise da proporção de dados agrupados ponderados, com heterogeneidade entre experimentos avaliada pelo índice relativo de inconsistência. Análises de sensibilidade e de subgrupos também foram realizadas. Foram incluídos um total de 25 artigos, representando 27 estudos de base populacional. A prevalência agrupada de AR resultou em 0,48% com 591.981 casos em uma população de 114.537.812 indivíduos (I2=99%). Brasil e Colômbia apresentaram as menores taxas de prevalência de AR 0,22% e 0,24%, respectivamente. A prevalência da AR na população indígena foi maior 1,45%, e estudos pelo método COPCORD relataram também as maiores taxas 1,07%.

Palavras-chave:
Artrite Reumatoide; Prevalência; América Latina; Acesso aos Serviços de Saúde; Metanálise como Assunto

Introduction

Rheumatoid arthritis (RA) is among the most prevalent chronic autoimmune and inflammatory diseases worldwide¹1 Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 3rd CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9):2569-2581.. When analyzing the 2010 Global Burden of Disease (GBD) initiative, overall estimated prevalence of RA was 0.24%²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.. RA affects the population mainly during their working age, limiting their functional capacity and generating a heavy economic burden for the individual and the community. A meta-analysis published by Dadoun et al.³3 Dadoun S, Zeboulon-Ktorza N, Combescure C, Elhai M, Rozenberg S, Gossec L, Fautrel B. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 2013; 80(1):29-33. showed that mortality from RA has decreased over the last five decades, increasing the life expectancy of RA patients, but also the complications of the disease. In recent decades, knowledge about the pathophysiology and laboratory and imaging tests for RA have positively evolved, resulting in improvements in RA treatment, outpatient care, and earlier diagnosis⁴4 Mota LM, Brenol CV, Palominos P, Pinheiro GR. Rheumatoid arthritis in Latin America: the importance of an early diagnosis. Clin Rheumatol 2015; 34(Supl. 1):S29-S44..

RA is spread worldwide, although regional variations in reported prevalence are significant, with the majority of estimates much higher that the GBD calculations. Although some African studies show a null disease prevalence rate⁵5 Silman AJ, Ollier W, Holligan S, Birrell F, Adebajo A, Asuzu MC, Thomson W, Pepper L. Absence of rheumatoid arthritis in a rural Nigerian population. J Rheumatol 1993; 20(4):618-622., such as the Democratic Republic of Congo, global reported estimates varying from 0.6% to 0.9%⁶6 Malemba JJ, Mbuyi-Muamba JM, Mukaya J, Bossuyt X, Verschueren P, Westhovens R. The epidemiology of rheumatoid arthritis in Kinshasa, Democratic Republic of Congo--a population-based study. Rheumatology (Oxford) 2012; 51(9):1644-1647.. A systematic review published in 2006⁷7 Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum 2006; 36(3):182-188. found a RA prevalence of 0.33% for Southern Europe, 0.50% for Northern European countries, and 0.35% for developing countries outside Africa. In China, these rates are around 0.42%. Although estimates of the global RA prevalence are about 1%, this overall rate may be influenced by the higher prevalence found in US and UK studies⁸8 Scublinsky D, Gonzalez CD. Quantifying Disease in Challenging Conditions: Incidence and Prevalence of Rheumatoid Arthritis. J Rheumatol 2016; 43(7):1263-1264.. It seems that RA occurrence varies among countries and regions of the world, with higher prevalence in Latin American countries with 1.25%⁹9 Rudan I, Sidhu S, Papana A, Meng SJ, Xin-Wei Y, Wang W, Campbell-Page RM, Demaio AR, Nair H, Sridhar D, Theodoratou E, Dowman B, Adeloye D, Majeed A, Car J, Campbell H, Wang W, Chan KY, Global Health Epidemiology Reference Group (GHERG). Prevalence of rheumatoid arthritis in low- and middle-income countries: A systematic review and analysis. J Glob Health 2015; 5(1):010409., and lower prevalence in Southern European countries⁸8 Scublinsky D, Gonzalez CD. Quantifying Disease in Challenging Conditions: Incidence and Prevalence of Rheumatoid Arthritis. J Rheumatol 2016; 43(7):1263-1264. and the French Antilles (Martinique)¹⁰10 Brunier L, Bleterry M, Merle S, Derancourt C, Polomat K, Dehlinger V, Deligny C, Jean-Baptiste G, Arfi S, Banydeen R, De Bandt M. Prevalence of rheumatoid arthritis in the French West Indies: Results of the EPPPRA study in Martinique. Joint Bone Spine 2017; 84(4):455-461.. No studies evaluating the prevalence of RA in South America were found.

Epidemiological data demonstrating regional variations contribute to understanding of how genetic and environmental factors may affect the development of RA in patients. However, the wide variation of the prevalence observed in different studies may also be associated with methodological differences between these studies. It is also important to take into consideration that genetic susceptibility to RA or to disease severity (e.g. presence of extra-articular manifestations, degree of radiographic joint destruction, production of rheumatoid factor) are associated with the histocompatibility antigens of the HLA-DR groups. However, this may vary with race. Caucasians are the most affected by HLA mutations, while Hispanic and African American patients present slightly or no associations with these genes¹¹11 Anaya JM, Correa PA, Mantilla RD, Jimenez F, Kuffner T, McNicholl JM. Rheumatoid arthritis in African Colombians from Quibdo. Semin Arthritis Rheum 2001; 31(3):191-198.. Additionally, is important to compare data from studies using similar methods based on the same disease identification criteria, to subsequently generate a valid global scenario for RA epidemiology⁸8 Scublinsky D, Gonzalez CD. Quantifying Disease in Challenging Conditions: Incidence and Prevalence of Rheumatoid Arthritis. J Rheumatol 2016; 43(7):1263-1264..

Further investigations on the epidemiological features of RA are paramount to developing optimal therapeutic guidelines. Thus, considering that RA prevalence may vary among regions worldwide and according to different sources of information, the aim of this study was to establish a pooled estimate of the RA prevalence in South America by means of a meta-analysis of the available epidemiologic studies.

Methods

This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Collaboration recommendations¹²12 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Cochrane; 2011.^,1313 Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. J Clin Epidemiol 2009; 62:1006-1012. so that all steps of screening of titles and abstracts, full-text appraisal, data extraction, and studies’ quality assessment were performed by two reviewers independently, with a third author to resolve discrepancies.

Search and study selection

PubMed, Lilacs, SciELO, Scopus, and Web of Science databases were systematically searched (updated May 2019), without restrictions for time-frame or language. A manual search in the reference lists of the included studies was also performed. Additionally, grey literature was searched through a systematic search in google.com.

Studies with original research design were included if they reported the prevalence of RA in any country or region of South America. The following exclusion criteria were applied: 1) studies not considering the prevalence of RA as main outcome; 2) articles published before 2000. In studies published in more than one article assessing prevalence on the same population, only the one with larger population was included.

During the screening phase (title and abstract reading), articles were excluded if considered irrelevant to the study goals. The full-text eligibility phase excluded articles that did not present enough data for the estimation of prevalence, or articles published in non-Roman characters.

Data extraction and quality assessment

The data extracted from each study included the following: type of study and year of publication; city/country of origin; population (number and ethnicity); definition of RA; data source (Community Oriented Program for the Control of the Rheumatic Diseases (COPCORD) methodology, clinical registries, or capture-recapture method); prevalence and year of estimation.

Although several tools have been developed to assess quality and risk of bias of primary studies, most of them are intended for interventional studies, being those relevant to observational studies generally unspecific or unsatisfactory and not widely used¹⁴14 Shamliyan T, Kane RL, Dickinson S. A systematic review of tools used to assess the quality of observational studies that examine incidence or prevalence and risk factors for diseases. J Clin Epidemiol 2010; 63(10):1061-1070.^,1515 Boyle M. Guidelines for evaluating prevalence studies. EBMH 1998; 1(2):37-40.. Considering that the validity of prevalence studies is a function of sampling, measurement, and analysis¹⁵15 Boyle M. Guidelines for evaluating prevalence studies. EBMH 1998; 1(2):37-40. and given the heterogeneity among studies design assessing RA prevalence, we assessed the quality of the included studies using a checklist adapted from Hoy et al.¹⁶16 Hoy D, Brooks P, Woolf A, Blyth F, March L, Bain C, Baker P, Smith E, Buchbinder R. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol 2012; 65(9):934-939. constituted by nine items. Briefly, these nine items refer to: study’s target population, sampling frame, random selection of the sample, non-response bias, data collection, case definition, instrument of measurement, mode of data collection, adequate numerator and denominator for the parameter of interest.

Statistical analyses

Proportion meta-analysis of weighted pooled (prevalence of RA) were performed considering both fixed and random-effect methods. Results were reported with a 95% confidence interval (CI). In addition, subgroup analyses considering population (ethnicity), year of publication, country of origin, and data source (clinical registries, COPCORD methodology or capture-recapture method) were performed by using Comprehensive Meta-Analysis (CMA) (Version 2.0, Biostat, Englewood, NJ).

Between-trial heterogeneity was assessed with the inconsistency relative index I2. This describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (i.e. chance). Values of I2>50% and p-values<0.05 indicates high and significant heterogeneity, that should be further investigated¹²12 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Cochrane; 2011.. We also conducted sensitivity analyses to test the robustness of the results and to evaluate the effect of individual studies on heterogeneity. The sensitivity analysis consisted of the hypothetical and sequential removal of one study from the meta-analysis. No study was permanently removed after the sensitivity analysis. Cumulative meta-analyses (sequence of meta-analyses performed adding one study at a time in chronological order) and meta-regression analyses considering time of publication as independent variable were also performed. The logit of the event rates as dependent variable were also performed. All graphs were built in Comprehensive Meta-Analysis (CMA) (Version 2.0, Biostat, Englewood, NJ).

Results

A total of 400 records were retrieved from the databases after duplicates removal. During the screening phase, 37 records were considered for full-text analysis, of which 25 articles, representing 27 population-based studies were included. Twelve articles were excluded after full-text appraisal because: n=4 published before 2000; n=3 not reported data on RA prevalence; n=3 were not an original research (e.g. review, comment); n=1 did not include patients from South America; n=1 included duplicated patients (Figure 1)¹¹11 Anaya JM, Correa PA, Mantilla RD, Jimenez F, Kuffner T, McNicholl JM. Rheumatoid arthritis in African Colombians from Quibdo. Semin Arthritis Rheum 2001; 31(3):191-198.^,1717 Spindler A, Bellomio V, Berman A, Lucero E, Baigorria M, Paz S, Garrone N, Torres AI, Romano O, Carraccio A, Leal O, Bazzano A, Vazquez D, Pera O, Arquez G, Valdez M, Lazaro H, Rengel S, Acosta E, Santana M. Prevalence of rheumatoid arthritis in Tucuman, Argentina. J Rheumatol 2002; 29(6):1166-1170.

18 Soriano ER, Carrio JH, Schpilberg M, Figar S, Imamura PM, Catoggio LJ. Incidence and prevalence of rheumatoid arthritis (RA) in a health management organization (HMO) in Argentina. Rheumatology (Oxford) 2003; 42(Supl. 1):127-131.

19 Senna ER, Barros AL, Silva EO, Costa IF, Pereira LV, Ciconelli RM, Ferraz MB. Prevalence of rheumatic diseases in Brazil: a study using the COPCORD approach. J Rheumatol 2004; 31(3):594-597.

20 Fabiani Muñoz IA. Prevalencia de Patología Músculo-esquelética Reumatoidea en el CESFAM "Cristo Vive", Santiago 2004. Santiago: Universidad de Chile; 2006.

21 Medina M, Acevedo-Vasquez E, Gutierrez C, Perich R, Sanchez-Torres A, De Leon DP, Pastor-Asurza C, Gamboa R, Alfaro J, Cucho M, Sanchez-Schwartz C. Low prevalence of rheumatoid arthritis in an urban mestizo population. J Clin Rheumatol 2006; 12(Supl. 4):S5.

22 Mestanza-Peralta M, Zurita-Salinas C, Armijos R. Prevalence of rheumatic diseases in a rural community in Ecuador. A community oriented program for control of rheumatic disorders (COPCORD). J Clin Rheumatol 2006; 12(Supl. 4):S6.

23 Gamboa R, Medina M, Acevedo E, Pastor C, Cucho J, Gutiérrez C, Ugarte M, Sánchez C, Perich R, Alfaro J, Sánchez A, La Madrid K, Zevallos F. Prevalencia de enfermedades reumatologicas y discapacidad en una comunidad urbano-marginal: resultados del primer estudio COPCORD en el Perú. Rev Peru Reumatol 2009; 15(1):40-46.

24 Scublinsky D, Venarotti H, Citera G, Messina OD, Scheines E, Rillo O, Arturi A, Hofman J, Somma LF, Casado G, Iannantuono RF, Gonzalez CD. The prevalence of rheumatoid arthritis in Argentina: a capture-recapture study in a city of Buenos Aires province. J Clin Rheumatol 2010; 16(7):317-321.

25 Granados Y, Cedeno L, Rosillo C, Berbin S, Azocar M, Molina ME, Lara O, Sanchez G, Peláez-Ballestas I. Prevalence of musculoskeletal disorders and rheumatic diseases in an urban community in Monagas State, Venezuela: a COPCORD study. Clin Rheumatol 2015; 34(5):871-877.

26 Machado-Alba JE, Ruiz AF, Medina Morales DA. The epidemiology of rheumatoid arthritis in a cohort of Colombian patients. Rev Colomb Reumatol 2015; 22(3):148-152.

27 Di WT, Vergara F, Bertiller E, Gallardo ML, Gandino I, Scolnik M, Martinez MJ, Schpilberg MG, Rosa J, Soriano ER. Incidence and Prevalence of Rheumatoid Arthritis in a Health Management Organization in Argentina: A 15-year Study. J Rheumatol 2016; 43(7):1306-1311.

28 Guevara-Pacheco S, Feican-Alvarado A, Sanin LH, Vintimilla-Ugalde J, Vintimilla-Moscoso F, Delgado-Pauta J, Lliguisaca-Segarra A, Dután-Erráez H, Guevara-Mosquera D, Ochoa-Robles V, Cardiel MH, Peláez-Ballestas I. Prevalence of musculoskeletal disorders and rheumatic diseases in Cuenca, Ecuador: a WHO-ILAR COPCORD study. Rheumatol Int 2016; 36(9):1195-1204.

29 Granados Y, Rosillo C, Cedeno L, Martinez Y, Sanchez G, Lopez G, Pérez F, Martínez D, Maestre G, Berbin S, Chacón R, Stekman I, Valls E, Peláez-Ballestas I. Prevalence of musculoskeletal disorders and rheumatic disease in the Warao, Kari'na, and Chaima indigenous populations of Monagas State, Venezuela. Clin Rheumatol 2016; 35(Supl. 1):53-61.

30 Caturegli G, Caturegli P. Disease prevalence in a rural Andean population of central Peru: a focus on autoimmune and allergic diseases. Auto Immun Highlights 2016; 7(1):3.

31 Díaz-Rojas JA, Dávila-Ramírez FA, Quintana-López G, Aristizábal-Gutiérrez F, Brown P. Prevalencia de artritis reumatoide en Colombia: una aproximación basada en la carga de la enfermedad durante el año 2005. Rev Colomb Reumatol 2016; 23(1):11-16.

32 Franco M, Avila Pedretti G, Morel Z, Cabrera-Villalba S, Melgarejo P, Elizaur JG, Albrecht TR, Paredes E, Mazzoleni J. Frecuencia de artritis reumatoide en el hospital central de IPS. Análisis preliminar. Rev Parag Reumatol 2016; 2(2):62-66.

33 Cuenta de Alto Costo. Situacion de la artritis reumatoide en Colombia 2016. Bogota: CAC; 2017.

34 Tolentino DSJ. Estudo da prevalência de doenças autoimunes na microrregião de saúde de Águas Formosas - Minas Gerais - Brasil [dissertação]. Teófilo Otoni: Universidade Federal dos Vales do Jequitinhonha e Mucuri; 2017.

35 Pelaez-Ballestas I, Granados Y, Quintana R, Loyola-Sanchez A, Julian-Santiago F, Rosillo C, Gastelum-Strozzi A, Alvarez-Nemegyei J, Santana N, Silvestre A, Pacheco-Tena C, Goñi M, García-García C, Cedeño L, Pons-Éstel BA, Latin American Study Group of Rheumatic Diseases in Indigenous Peoples (GLADERPO). Epidemiology and socioeconomic impact of the rheumatic diseases on indigenous people: an invisible syndemic public health problem. Ann Rheum Dis 2018; 77(10):1397-1404.

36 Quintana R, Goni M, Mathern N, Jorfen M, Conti S, Nieto R, Sanabria A, Prigione C, Silvestre AMR, García V, Pons-Estel G, Cervera R, García C, Peláez-Ballestas I, Alarcón GS, Pons-Estel BA. Rheumatoid arthritis in the indigenous qom population of Rosario, Argentina: aggressive and disabling disease with inadequate adherence to treatment in a community-based cohort study. Clin Rheumatol 2018; 37(9):2323-2330.

37 Vega-Hinojosa O, Cardiel MH, Ochoa-Miranda P. Prevalence of musculoskeletal manifestations and related disabilities in a Peruvian urban population living at high altitude. COPCORD Study. Stage I. Reumatol Clin 2018; 14(5):278-284.

38 Londoño J, Peláez Ballestas I, Cuervo F, Angarita I, Giraldo R, Rueda JC, Ballesterosa JG, Baqueroa R, Foreroc E, Cardield M, Saldarriagaa E, Vásqueza A, Ariasa S, Valeroa L, Gonzáleza C, Ramíreze J, Toroe C, Santos AM. Prevalencia de la enfermedad reumática en Colombia, según estrategia COPCORD-Asociación Colombiana de Reumatología. Estudio de prevalencia de enfermedad reumática en población colombiana mayor de 18 años. Rev Colomb Reumatol 2018; 25(4):245-256.

39 Palmezano-Díaz JM, Figueroa-Pineda CL, Rodríguez-Amaya RM, Plazas-Rey LK. Prevalencia y caracterización de las enfermedades autoinmunitarias en pacientes mayores de 13 años en un hospital de Colombia. Med Int Mex 2018; 34(4):522-535.^-4040 Fernández-Ávila DG, Rincón-Riaño DN, Bernal-Macías S, Gutiérrez Dávila JM, Rosselli D. Prevalencia de la artritis reumatoide en Colombia según información del Sistema Integral de Información de la Protección Social. Rev Colomb Reumatol 2019; 26(2):83-87..

These studies were published between 2001 and 2019 and conducted in Argentina (n=6 studies), Brazil (n=2), Chile (n=1), Colombia (n=7), Ecuador (n=2), Paraguay (n=1), Peru (n=4), and Venezuela (n=4). Seven records (25.0%) evaluated RA in specific ethnicities (e.g. African Colombians, Amerindians, Indigenous). The ACR 1987 revised criteria was used for patient’s diagnosis in 12 studies (37.5%), while seven (29.2%) mentioned the ICD-10 for disease classification. Clinical registries were the main data source (54.2% of studies), followed by COPCORD methodology (41.7%) and capture-recapture method (8.3%). The main characteristics of the included studies are presented in Chart 1. The quality assessment showed and overall moderate risk of bias for around 60% of studies. Most of studies (74%) did not present a sampling frame truly or closely representative of the target population. Census or random selection sampling were undertaken in 40% of studies. The numerator and denominator for the calculation of prevalence were properly described in only one third of studies. No significant problems were observed for the domains of parameter of interest measurement and subjects’ data collection.

Overall, prevalence of RA was estimated in 0.48% [95%CI 0.38%-0.62%] (with high between-trial heterogeneity: I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=99%) with 591,981 cases in a population of 114,537,812 individuals (denominator population) (Figure 2). Sensitivity analyses with the hypothetical removal of trials showed few reductions in the heterogeneity (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322. values ranging from 86% to 99%) with similar effect sizes. Possible reasons for this heterogeneity may include population characteristics (e.g. race, age), disease features (e.g. duration of RA, diagnostic and classification criteria), sampling, case index definition, study design, and methodology.

The results for subgroup analyses are demonstrated in Table 1. Analyses showed that Brazil and Colombia presented the lowest rates of RA prevalence (0.22% [0.05%-0.91%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=95% and 0.24% [0.15%-0.39%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=99% respectively), while Ecuador followed by Venezuela had the higher rates (0.89% [0.69%-1.16%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=0% and 0.86% [0.41%-1.77%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=83%, respectively). Higher rates of RA prevalence were also obtained for the subgroup of indigenous population (1.45% [0.88%-2.37%]; I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=85%) when compared to the overall population (0.44% [0.33%-0.58%]; I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=99%) (p<0.001). I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322. values remained high (>80%) even when conducting sensitivity analyses.

Lower rates of RA prevalence were found in studies using clinical registries as data source (0.26% [0.18%-0.37%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=99%) compared to studies using a population-based design like the COPCORD methodology (1.07% [0.74%-1.55%], I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=90%) (p<0.001). Further analyses considering data sources by country (Table 2) confirm these findings. Argentina had an event rate of 0.21% [0.18%-0.25%] (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=75%) when using clinical registries as source, compared to an estimate of 2.76% [2.22%-3.34%] (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=20%) given by COPCORD. Similarly, the prevalence rates for Peru were of 0.32% [0.31%-0.33%] (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=0%) and 0.82% [0.33%-2.01%] (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.=80%), respectively.

Cumulative analyses and meta-regression of events rates showed an increase in the prevalence of RA over the past years (slope of 0.082; p<0.001) as demonstrated in Figure 3. Prevalence varied from around 0.02% to 0.10% between 2001 and 2003, reaching around 0.20% in 2006, to more than 0.30% after 2015.

Discussion

We found a polled RA prevalence in South America of about 0.5%, with country variations ranging from 0.2% to 2.4%. We also found higher prevalence estimates when used a consistent population-based methodology like COPCORD, compared to non-population-based prevalence estimates obtained from registry analyses or capture-recapture method. These estimates are in accordance with the range of estimates in other studies worldwide.

Geographic variations are widely observed in the prevalence rate of RA, possibly due to the combination of behavioral, climatic, environmental, genetic and clinical presentation of the disease. Even, within ethnic groups, the prevalence of RA varies according to geographic area of residence. Prevalence reported for southern European countries range from 0.31% to 0.38%⁴¹41 Marinovic I, Kaliterna DM, Smoljanovic M, Radic M, Cecuk-Jelicic E, Bogdanic D, Pivalica D. The prevalence of rheumatoid arthritis in Split-Dalmatia County in southern Croatia is 0.24. Joint Bone Spine 2016; 83(4):457-458.. Additionally, patients in southern Europe, especially in the Mediterranean region, have fewer extra-articular and radiological manifestations, which may be associated with the Mediterranean diet and climatic factors that have protective effects on the development of the disease⁴²42 Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005; 4(3):130-136..

The influence of genetic factors on the appearance of RA is evident at individual level, but also at population level. To date, more than 100 genetic loci have been associated with RA, however, the relationship of all these loci to the disease remains to be elucidated⁴³43 Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra H-J, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJH, van Riel PLCM, van de Laar MAFJ, Guchelaar H-J, Huizinga TWJ, Dieudé P, Mariette X, Bridges Jr SL, Zhernakova A, Toes REM, Tak PP, Miceli-Richard C, Bang S-Y, Lee H-S, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapää-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, RACI consortium, GARNET consortium, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae S-C, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506(7488):376-381.. It is known that class II major antigens HLA-DR have been implicated in the pathogenesis of RA and that reidentification of PADI4 was associated with significant risk to RA in Europeans. HLA-DRB1 alleles have been reported in Native Americans, Mexican American ancestry, Colombian population, Chilean population, Peruvian population, Brazilian population and Mexican Mestizo population with a larger proportion of European ancestry⁴³43 Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra H-J, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJH, van Riel PLCM, van de Laar MAFJ, Guchelaar H-J, Huizinga TWJ, Dieudé P, Mariette X, Bridges Jr SL, Zhernakova A, Toes REM, Tak PP, Miceli-Richard C, Bang S-Y, Lee H-S, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapää-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, RACI consortium, GARNET consortium, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae S-C, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014; 506(7488):376-381.

44 Kurko J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z. Genetics of rheumatoid arthritis - a comprehensive review. Clin Rev Allergy Immunol 2013; 45(2):170-179.^-4545 Castro-Santos P, Diaz-Pena R. Genetics of rheumatoid arthritis: a new boost is needed in Latin American populations. Rev Bras Reumatol Engl Ed 2016; 56(2):171-177.. Duran et al.⁴⁶46 Duran J, Massardo L, Llanos C, Jacobelli S, Burgos PI, Cisternas M, Iruretagoyena M, Armstrong M, Aguilera R, Radrigán F, Martinez ME, Passi-Solar A, Riedemann P, Crisóstomo N, Cifuentes C, Hagedorn L, Cisternas A, Vasquez N, Margozzini P, ENS2017 Study Group. The prevalence of Rheumatoid Arthritis in Chile: a nation-wide study performed as part of the National Health Survey (ENS 2016-17). J Rheumatol 2020; 47(7):951-958. observed a national RA prevalence of 0.6% in the Chilean population, which was similar the Spanish prevalence of 0.5% reported by Carmona et al.⁴⁷47 Carmona L, Villaverde V, Hernandez-Garcia C, Ballina J, Gabriel R, Laffon A. The prevalence of rheumatoid arthritis in the general population of Spain. Rheumatology (Oxford) 2002; 41(1):88-95.. Duran et al.⁴⁶46 Duran J, Massardo L, Llanos C, Jacobelli S, Burgos PI, Cisternas M, Iruretagoyena M, Armstrong M, Aguilera R, Radrigán F, Martinez ME, Passi-Solar A, Riedemann P, Crisóstomo N, Cifuentes C, Hagedorn L, Cisternas A, Vasquez N, Margozzini P, ENS2017 Study Group. The prevalence of Rheumatoid Arthritis in Chile: a nation-wide study performed as part of the National Health Survey (ENS 2016-17). J Rheumatol 2020; 47(7):951-958. supported theses coincident rates on the predominant Spanish ancestry in Chile.

The prevalence of RA does not behave homogeneously in South America, as observed in our meta-analysis (I²2 Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, Williams B, Gabriel S, Lassere M, Johns N, Buchbinder R, Woolf A, March L. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014; 73(7):1316-1322.>90%), perhaps because of the heterogeneous ethnic origins of the populations constituting this region (i.e. degree of admixture according to the major ancestry population component). In several countries, indigenous populations have higher RA prevalence, with estimates ranging from 2 to 6 times higher than non-indigenous populations. Indigenous populations from Canada, United States, Australia, and New Zealand presented RA prevalence ranging from 0.7 to 6.8%⁴⁸48 McDougall C, Hurd K, Barnabe C. Systematic review of rheumatic disease epidemiology in the indigenous populations of Canada, the United States, Australia, and New Zealand. Semin Arthritis Rheum 2017; 46(5):675-686.. The adjusted RA prevalence in the Central Canadian indigenous population is more than double that of the general population⁴⁹49 Hitchon CA, Khan S, Elias B, Lix LM, Peschken CA. Prevalence and Incidence of Rheumatoid Arthritis in Canadian First Nations and Non-First Nations People: A Population-Based Study. J Clin Rheumatol 2020; 26(5):169-175.. A meta-analysis conducted in Mexico found RA prevalence from 0.28% to 0.7% in the indigenous population⁵⁰50 Galarza-Delgado DA, Azpiri-Lopez JR, Colunga-Pedraza IJ, Cardenas-de la Garza JA, Vera-Pineda R, Wah-Suarez M, Arvizu-Rivera RI, Martínez-Moreno A, Ramos-Cázares RE, Torres-Quintanilla FJ, Valdovinos-Bañuelos A, Esquivel-Valerio JA, Garza-Elizondo MA. Prevalence of comorbidities in Mexican mestizo patients with rheumatoid arthritis. Rheumatol Int 2017; 37(9):1507-1511.. Previous researches show that important phenotypic differences may exist between indigenous and non-indigenous populations with rheumatic diseases. For example, an aboriginal cohort with RA followed at a tertiary care center in Canada was more frequently seropositive and had worse HAQ (Health assessment questionnaire) scores than Caucasian patients. American Indian and Alaska Native populations with RA also present more extra-articular manifestations, erosive disease and more severe radiographic findings, which are associated with a high frequency of HLA-B27 gene and subtype HLA-DRB1*1402. Additionally, indigenous population share similarities in difficulties in access to healthcare coverage, which may influence clinical outcomes³⁵35 Pelaez-Ballestas I, Granados Y, Quintana R, Loyola-Sanchez A, Julian-Santiago F, Rosillo C, Gastelum-Strozzi A, Alvarez-Nemegyei J, Santana N, Silvestre A, Pacheco-Tena C, Goñi M, García-García C, Cedeño L, Pons-Éstel BA, Latin American Study Group of Rheumatic Diseases in Indigenous Peoples (GLADERPO). Epidemiology and socioeconomic impact of the rheumatic diseases on indigenous people: an invisible syndemic public health problem. Ann Rheum Dis 2018; 77(10):1397-1404.^,5151 Hurd K, Barnabe C. Systematic review of rheumatic disease phenotypes and outcomes in the Indigenous populations of Canada, the USA, Australia and New Zealand. Rheumatol Int 2017; 37(4):503-521.^,5252 Peschken CA, Hitchon CA, Robinson DB, Smolik I, Barnabe CR, Prematilake S, El-Gabalawy HS. Rheumatoid arthritis in a north american native population: longitudinal followup and comparison with a white population. J Rheumatol 2010; 37(8):1589-1595..

Conversely, several studies showed that the frequencies of genetic alleles that increase RA susceptibility are more prevalent in Caucasians than in Africans. Other studies demonstrated that several polymorphisms associated with RA were almost undetectable in West and Central Africa⁵³53 Viatte S, Flynn E, Lunt M, Barnes J, Singwe-Ngandeu M, Bas S, Barton A, Gabay C. Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease. Arthritis Res Ther 2012; 14(6):R239.^,5454 Singwe-Ngandeu M, Finckh A, Bas S, Tiercy JM, Gabay C. Diagnostic value of anti-cyclic citrullinated peptides and association with HLA-DRB1 shared epitope alleles in African rheumatoid arthritis patients. Arthritis Res Ther 2010; 12(2):R36.. RA is poorly reported in black Africans in West and Central Africa and its prevalence is still unknown or based in very old studies. One study in South Africa⁵⁵55 Brighton SW, de la Harpe AL, van Staden DJ, Badenhorst JH, Myers OL. The prevalence of rheumatoid arthritis in a rural African population. J Rheumatol 1988; 15(3):405-408. that investigated rural population showed a prevalence of RA of 0.0026%. Another study in a rural population of Nigeria⁵5 Silman AJ, Ollier W, Holligan S, Birrell F, Adebajo A, Asuzu MC, Thomson W, Pepper L. Absence of rheumatoid arthritis in a rural Nigerian population. J Rheumatol 1993; 20(4):618-622. found a zero prevalence of the disease. After the redefinition of diagnostic criteria of RA that identify patients with RA at an early stage of the disease, these old studies may not be useful any more⁵⁶56 Nair B, Taylor-Gjevre R, Wu L, Jin S, Quail JM. Incidence and prevalence of rheumatoid arthritis in Saskatchewan, Canada: 2001-2014. BMC Rheumatol 2019; 3:28..

When reliable, prevalence estimates are a good way to describe the burden of RA in a specific population⁵⁷57 Barnabe C, Jones CA, Bernatsky S, Peschken CA, Voaklander D, Homik J, Crowshoe LF, Esdaile JM, El-Gabalawy H, Hemmelgarn B. Inflammatory Arthritis Prevalence and Health Services Use in the First Nations and Non-First Nations Populations of Alberta, Canada. Arthritis Care Res (Hoboken) 2017; 69(4):467-474.. In our meta-analysis we found different methods to obtain data for calculating prevalence of RA. Registries, such as clinical records and health insurance databases, are data sources that contain a large amount of real-world data collected for a population over a period of time. Apart from the potential inaccuracies originated by poor recording practices, registries may produce biased information due to sub-diagnose or insufficient coverage of care plans. But reliability of registries is especially affected by their dependence on the stability of the definition of RA cases through the time⁵⁶56 Nair B, Taylor-Gjevre R, Wu L, Jin S, Quail JM. Incidence and prevalence of rheumatoid arthritis in Saskatchewan, Canada: 2001-2014. BMC Rheumatol 2019; 3:28..

Capture-recapture is usually presented as a quick and inexpensive method that allows correct prevalence estimates, even if data come from incomplete sources. However, this method should be carefully used, especially in populations with very low prevalence rates⁵⁸58 Tilling K. Capture-recapture methods--useful or misleading? Int J Epidemiol 2001; 30(1):12-14.. Reliability of capture-recapture depends also of counting with diversified health data sources that allow covering different segments of the population⁵⁹59 Coeli CM, Veras RP, Coutinho ESF. Capture-recapture methodology: an option for surveillance of non-communicable diseases in the elderly. Cad Saude Publica 2000; 16(4):1071-1082..

The International League of Associations for Rheumatology together with the World Health Organization launched the Community Oriented Program for Control of Rheumatic Diseases (COPCORD) initiative with the aim of gathering data on pain and disability associated to rheumatic diseases by using low-cost means (http://copcord.org/). In our meta-analysis, the COPCORD studies found higher prevalence than the rest of the epidemiological studies. This is probably because COPCORD method, as any population-based study, overcomes the limitations of registry studies associated to under-estimation due to sub-optimal medical care⁶⁰60 Vargas RB, Cardiel MH. Rheumatoid arthritis in Latin America. Important challenges to be solved. Clin Rheumatol 2015; 34(Supl. 1):S1-S3.. In fact, assuming that the actual RA prevalence in South America coincides with the prevalence of RA diagnosed individuals may be completely wrong due to the effect of ignoring potential RA disease under-diagnose. To evaluate the quality of the RA care, further studies should identify the prevalence-diagnose-treatment gap.

Conclusions

Our meta-analysis identifies a pooled prevalence of RA in South America of 0.48%, ranging from 0.22% in Brazil to 2.40% in Paraguay. Indigenous populations presented higher prevalence than any other ethnic group. COPCORD studies (population-based design) obtained a higher and more reliable prevalence estimates than registry data.

References

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