Rheumatoid arthritis and metabolic syndrome

Abstracts

Nos últimos 20 anos, tem sido demonstrado que a artrite reumatoide (AR) pode reduzir a expectativa de vida de 3 a 10 anos em comparação com a população em geral. Atualmente, a doença cardiovascular (DCV) é a principal causa de morte nos pacientes com AR, e a ocorrência de infarto agudo do miocárdio pode ser até quatro vezes maior nesses pacientes. A resposta inflamatória sistêmica de etiologia autoimune, somada à presença de síndrome metabólica (SM), torna duas vezes maior o risco de DCV fatal ou não fatal e da aterosclerose coronariana, independentemente da idade e sexo. A artrite reumatoide tem sido associada a aumento da prevalência de SM, mas o papel das diferentes características da doença, tais como a duração da doença, atividade e tratamento com glucocorticoides não estão bem definidos. O objetivo deste trabalho é revisar a prevalência de SM e os fatores implicados no desenvolvimento de aterosclerose nos pacientes com AR, avaliando os aspectos clínicos da AR e sua associação com o desenvolvimento de SM.

síndrome X metabólica; artrite reumatoide; doenças cardiovasculares

REVIEW ARTICLE

^IMaster in Medical Sciences by the UFRGS; Rheumatologist at Hospital Universitário de Santa Maria

^IIPhD in Medical Sciences by the UFRGS; Coordinator of the Hospital de Clínicas de Porto Alegre

^IIIProfessor and Chief of the Department of Internal Medicine at UFRGS; PhD in Medicine by the UFRGS

^IVProfessor of the Department of Internal Medicine at Medical School of the UFRGS; PhD in Immunology by the Shimane University, Japan; Chief of the Rheumatology Service of the HCPA

Correspondence to

ABSTRACT

In the past 20 years, the life expectancy of patients with rheumatoid arthritis (RA) has been shown to be reduced by three to ten years as compared to that of the general population. Currently, cardiovascular disease (CVD) is the major cause of death in patients with RA, and acute myocardial infarction can be up to four times more frequent in these patients. The autoimmune systemic inflammatory response, along with the presence of metabolic syndrome (MetS), doubles the risk for fatal or non-fatal CVD and coronary atherosclerosis, regardless of age and sex. Rheumatoid arthritis has been associated with increased prevalence of MetS, but its role in the different characteristics of the disease, such as disease duration, activity, and treatment with glucocorticoids, is not well defined. This study aimed at reviewing the prevalence of MetS and the factors implicated in the development of atherosclerosis in RA patients, assessing the clinical aspects of RA and its association with the development of MetS.

Keywords: metabolic syndrome X, rheumatoid arthritis, cardiovascular diseases.

INTRODUCTION

Rheumatoid arthritis (RA) is a systemic inflammatory disorder characterized by chronic symmetric and erosive synovitis that affects preferentially peripheral joints.¹ Patients with RA have a reduced life expectancy,² which is associated with an increased risk for cardiovascular events.^3,4 They have a four-fold increased frequency of acute myocardial infarction.⁵ Accelerated coronary³ and extracoronary² atherosclerosis is a characteristic of RA, and its pathogenesis has not been clearly defined.⁶ The high prevalence of traditional cardiovascular risk factors and the systemic inflammatory process play a role in this pathogenesis. There is evidence of an inflammatory basis for atherosclerosis, which has led many researchers to study the relationship between systemic inflammatory conditions, such as RA, and the risk for coronary heart disease.^7-9 Metabolic syndrome (MetS), a set of cardiovascular risk factors (such as central obesity, dyslipidemia, hypertension, and hyperglycemia), has been assessed aiming at predicting the risk for cardiovascular disease (CVD).³ There is evidence showing the association between RA, its inflammatory activity, and MetS,^2,3 but the results on the prevalence of this syndrome in RA are conflicting.^2,3,6,10,11

This study aimed at reviewing the prevalence of MetS and the factors involved in the development of atherosclerosis in RA patients, assessing the clinical aspects of RA and their association with the development of MetS.

DEFINITION CRITERIA OF METABOLIC SYNDROME

Metabolic syndrome can increase up to two fold the risk for CVD.¹² The most accepted hypothesis for the development of MetS indicates insulin resistance (IR) as the major pathophysiological mediator.¹³

There have been several attempts to define MetS in literature (Table 1). The World Health Organization (WHO) established in 1999 the criteria for defining MetS (modified in 2004).¹⁴ Alternative definitions have been subsequently proposed by the European Group for the Study of Insulin Resistance (EGIR)¹⁵ in 1999 and by the Adult Treatment Panel III of the National Cholesterol Education Program (NCEP ATP III) - American Heart Association (AHA) in 2001. The NCEP III was last updated in 2005.¹⁶ The American Association of Clinical Endocrinologists (AACE),¹⁷ in 2003, and the International Diabetes Federation (IDF),¹⁸ in 2004, have also proposed their criteria for defining MetS.

All definitions include measuring systemic blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), and fasting glycemia. They differ regarding the cutoff points of their components and the criteria of obesity. The WHO and EGIR definitions require the presence of IR in the first, and IR or hyperinsulinemia in the second. The definition of the NCEP-ATP III is based only on the number of abnormalities,³ while the IDF definition is based on central obesity, which requires an increased waist circumference. The AACE definition of MetS requires high risk for IR or body mass index (BMI) > 25 kg/m²or waist > 102 cm (men)/ > 88 cm (women).

PREVALENCE OF METABOLIC SYNDROME IN BRAZIL

A study carried out by Nakazone et al.¹⁹in the city of São José do Rio Preto, São Paulo state, in 2007, assessed 340 individuals (200 patients and 140 controls), paired for sex and age. The patients were on regular follow-up with a cardiologist, and the presence of risk factors for CVD was considered, aiming at primary or secondary prevention. Individuals with no routine cardiology follow-up were included in the control group. According to the NCEP-ATPIII (2001) criteria, 35.5% of patients and 8.6% of controls (P < 0.0001) had MetS. The IDF criteria evidenced MetS in 46% of patients and in 17.9% of controls (P < 0.0001).

Another Brazilian study, assessing the existence of an association between periodontal disease and MetS in 1,315 Japanese-Brazilians aged between 30 and 92 years, regardless of oral health conditions, has reported a 54% prevalence of MetS according to the NCEP 2001 definition.²⁰

In 2004, Velásquez-Meléndez et al.²¹ carried out a cross-sectional population-based study in Virgem das Graças, a rural community located in Vale do Jequitinhonha, state of Minas Gerais. The study comprised 251 individuals (117 men and 134 women), whose ages ranged from 20 to 88 years. The prevalence of MetS according to the NCEP 2001 definition was 21.6% (7.7% for men and 33.6% for women). The overall prevalence adjusted for age was 19.0%.

In 2006, a population-based study conducted in the rural district of Cavunge, in the semi-arid region of the state of Bahia, assessed the prevalence of MetS according to the NCEP/ATPIII 2001 criteria in a random sample consisting of 240 individuals (102 men and 138 women; age range, 25 to 87 years). The raw prevalence of MetS was 30.0%, and, after adjusting for age, 24.8%.²²

Salaroli et al.²³ have reported a 29.8% prevalence of MetS (without difference between sexes) in a random sample of 1,663 individuals (25-64 years) in the city of Vitoria, state of Espírito Santo, according to the NCEP/ATPIII 2001 criteria.

CRITICAL OVERVIEW OF METABOLIC SYNDROME

In addition to the sum of the individual components of MetS,² this cluster of risk factors is believed to play an important role in increasing the risk for CVD. Likewise, the existence of a single pathophysiological basis, IR,³is believed to explain the syndrome. However, a consensus about it has not been achieved.

The American Diabetes Association and the European Association for the Study of Diabetes have issued a joint declaration questioning the classification of the components of MetS as a true "syndrome". The arguments were as follows: lack of definition clarity, with different criteria in existing definitions; different and multiple phenotypes included in MetS, with consequent different treatment strategies; lack of a consistent evidence basis for entering several components in the definitions; inclusion of patients with clinical CVD or diabetes as part of the syndrome, which is intended to define risk for these diseases; unclear pathogenesis linking the components of MetS: there is the possibility that IR is not the underlying condition of all factors, and it is not a consistent finding in some definitions; other risk factors for CVD, which are not components of MetS, such as inflammatory markers, may carry an equal or greater risk; and, finally, the MetS-associated risk for CVD has not shown to be greater than the sum of the individual components.²⁴

Despite questions about the existence of MetS, it is undoubtedly paramount to identify the presence of its components and establish the adequate management strategies so that the morbidity and mortality associated with diabetes and CVD can be reduced.²⁵

The etiology of MetS is unknown, but it is likely to involve a complex interaction of genetic, environmental, and metabolic factors. Results of several studies have suggested that the pro-inflammatory state can contribute to the development of MetS.²⁰

METABOLIC SYNDROME IN RHEUMATOID ARTHRITIS

The interest in identifying MetS in patients with RA has emerged recently, justified by the need to better understand the determinant factors of CVD in these patients (Table 2).

In 2002, the first study assessing the hypothesis that the increased prevalence of interrelated cardiovascular risk (CV risk factors) factors determines the presence of MetS in RA had patients with osteoarthritis (OA) as the control group. The authors reported that more patients with RA had IR and low HDL levels as compared with patients with OA, and both were directly associated with C-reactive protein levels. Moreover, IR, low HDL levels, hypertriglyceridemia, and hypertension were associated with each other in the rheumatoid group, which was not observed in patients with OA.²⁶

To assess the effects of glucocorticoids on CVD of patients with RA, Dessein et al.⁵ have tested the effects of glucocorticoids on traditional CV risk factors factors. The use of prednisone and its frequent intramuscular, intra-articular, and intravenous doses have been associated with the presence of IR (P < 0.05). The use of glucocorticoids has not been associated with obesity, dyslipidemia, or hypertension. In 2006, the same research team assessed the association of MetS-related CV risk factors factors with the presence of subclinical atherosclerosis using ultrasound measurement of plaques and the common carotid intima and media layer thickness. Hypertension, IR, and hypertriglyceridemia were independent risk factors for subclinical atherosclerosis (P = 0.02, 0.04, and 0.05, respectively). In this study, individual risk factors were more strongly associated with subclinical atherosclerosis than with the MetS definitions.¹⁰

In 2008, Chung et al.² demonstrated for the first time an increase in MetS prevalence in patients with RA when compared with controls adjusted for age, race, and sex. Using the WHO definition, the frequency of MetS was greater in patients with long-term disease (42%) when compared to patients with early arthritis (30%) and controls (11%) (P < 0.001). The authors also assessed the presence of atherosclerosis using detection of coronary calcifications on electron beam computed tomography. In RA group, patients with MetS according to the WHO definition were at an increased risk for higher coronary artery calcification scores, regardless of age and sex (OR = 2.02; 95% CI: 1.03-3.97; P = 0.04).

Some authors have found conflicting results regarding the aforementioned studies. Karvounaris et al.³ reported no statistically significant difference between cases and controls regarding the presence of MetS. The authors have studied 200 patients with RA and 400 controls adjusted for age and sex. The total prevalence of MetS, according to the NCEP 2001 definition, was 44% in patients with RA and 41% in controls (P = 0.5). In another study, La Montagna et al.⁶ assessed 45 patients with RA and 48 controls with no systemic rheumatologic disease. The prevalence of MetS, according to the updated NCEP definition, was 55.5% in patients with RA and 45.8% in patients without RA. In the study, no significant difference was observed between cases and controls.

In 2010, North-American researchers assessed the presence of CV risk factors factors and the NCEP III criteria for MetS in a case-control study with 131 patients with RA and 121 controls.²⁷ The difference in prevalence of MetS was not statistically significant between patients and controls (36% versus 27%; P = 0.12; respectively). These authors quantified the visceral and subcutaneous fat by use of computed tomography. The abdominal fat distribution differed significantly depending on RA activity, and was more significantly associated with CV risk factors factors in patients than in controls.

Non-controlled studies have also assessed the prevalence of MetS in RA. Elkan et al.,¹¹ differently from the previous studies, used the IDF criteria for determining the prevalence of MetS in 80 patients (61 women and 19 men) with RA. They have reported a MetS prevalence of 20% for women and 63% for men. In 2009, Toms et al.²⁸ assessed the prevalence of MetS in 400 patients with RA using five definitions (NCEP 2004 and 2001, IDF, WHO, and EGIR). The highest prevalence was 45.3% according to IDF, and the lowest prevalence was 12.1% according to EGIR.

CONCLUSIONS

Based on current knowledge, one can state that patients with RA are at a higher risk for developing CVD than general population. Studies about the prevalence of MetS in this population of patients have not achieved definitive conclusions, although its presence has been directly associated with a worse prognosis and disease activity. By itself, the later aspect suggests that a better control of underlying disease inflammatory process may improve both articular and CV prognoses in these patients. Monitoring and early identification of CV risk factors factors should be a necessary and constant preoccupation of rheumatologists caring for patients with RA.

REFERENCES

• ¹
  Kelley WN, Ruddy, S., Sledge, C.B. eds. Textbook of rheumatology. 5 ed. Philadelphia: WB Saunders, 1997.
• ²
  Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis 2008; 196(2):756-63.
• ³
  Karvounaris SA, Sidiropoulos PI, Papadakis JA, Spanakis EK, Bertsias GK, Kritikos HD et al. Metabolic syndrome is common among middle-to-older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross-sectional, controlled, study. Ann Rheum Dis 2007; 66(1):28-33.
• ⁴
  del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44(12):2737-45.
• ⁵
  Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol 2004; 31(5):867-74.
• ⁶
  La Montagna G, Cacciapuoti F, Buono R, Manzella D, Mennillo GA, Arciello A et al. Insulin resistance is an independent risk factor for atherosclerosis in rheumatoid arthritis. Diab Vasc Dis Res 2007; 4(2):130-5.
• ⁷
  Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2005; 52(2):402-11.
• ⁸
  Brenol CV, Monticielo OA, Xavier RM, Brenol JC. Rheumatoid arthritis and atherosclerosis. Rev Assoc Med Bras 2007; 53(5):465-70.
• ⁹
  Torigoe DY, Laurindo IdMMe. Artrite reumatóide e doenças cardiovasculares. Rev Bras Reumatol 2006; 46:60-6.
• ¹⁰
  Dessein PH, Tobias M, Veller MG. Metabolic syndrome and subclinical atherosclerosis in rheumatoid arthritis. J Rheumatol 2006; 33(12):2425-32.
• ¹¹
  Elkan AC, Hakansson N, Frostegard J, Cederholm T, Hafstrom I. Rheumatoid cachexia is associated with dyslipidemia and low levels of atheroprotective natural antibodies against phosphorylcholine but not with dietary fat in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2009; 11(2):R37.
• ¹²
  Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CD, Bouter LM et al. Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn Study. Circulation 2005; 112(5):666-73.
• ¹³
  Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365(9468):1415-28.
• ¹⁴
  Reilly MP, Wolfe ML, Rhodes T, Girman C, Mehta N, Rader DJ. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation 2004; 110(7):803-9.
• ¹⁵
  Beck-Nielsen H. General characteristics of the insulin resistance syndrome: prevalence and heritability. European Group for the study of Insulin Resistance (EGIR). Drugs 1999; 58 Suppl 1:7-10, discussion 75-82.
• ¹⁶
  16. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112(17):2735-52.
• ¹⁷
  Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003; 9(3):237-52.
• ¹⁸
  Alberti KG, Zimmet P, Shaw J. Metabolic syndrome: a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006; 23(5):469-80.
• ¹⁹
  Nakazone MA, Pinheiro A, Braile MC, Pinhel MA, de Sousa GF, Pinheiro S, Jr. et al. Prevalence of metabolic syndrome using NCEP-ATPIII and IDF definitions in Brazilian individuals. Rev Assoc Med Bras 2007; 53(5):407-13.
• ²⁰
  Borges PK, Gimeno SG, Tomita NE, Ferreira SR. Prevalence and characteristics associated with metabolic syndrome in Japanese-Brazilians with and without periodontal disease. Cad Saude Publica 2007; 23(3):657-68.
• ²¹
  Velasquez-Melendez G, Gazzinelli A, Correa-Oliveira R, Pimenta AM, Kac G. Prevalence of metabolic syndrome in a rural area of Brazil. São Paulo Med J 2007; 125(3):155-62.
• ²²
  de Oliveira EP, de Souza ML, de Lima MD. Prevalence of metabolic syndrome in a semi-arid rural area in Bahia. Arq Bras Endocrinol Metabol 2006; 50(3):456-65.
• ²³
  Salaroli LB, Barbosa GC, Mill JG, Molina MC. Prevalence of metabolic syndrome in population-based study, Vitoria, ES-Brazil. Arq Bras Endocrinol Metabol 2007; 51(7):1143-52.
• ²⁴
  Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28(9):2289-304.
• ²⁵
  Meigs JB. Metabolic syndrome: in search of a clinical role. Diabetes Care 2004; 27(11):2761-3.
• ²⁶
  Dessein PH, Stanwix AE, Joffe BI. Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis. Arthritis Res 2002; 4(5):R5.
• ²⁷
  Giles JT, Allison M, Blumenthal RS, Post W, Gelber AC, Petri M et al. Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum 2010; 62(11):3173-82.
• ²⁸
  Toms TE, Panoulas VF, John H, Douglas KM, Kitas GD. Methotrexate therapy associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60- more than just an anti-inflammatory effect? A cross sectional study. Arthritis Res Ther 2009; 11(4):R110.

Rheumatoid arthritis and metabolic syndrome

Viviane Roseli da Cunha^I; Claiton Viegas Brenol^II; João Carlos Tavares Brenol^III; Ricardo Machado Xavier^IV

Publication Dates

• Publication in this collection
  20 May 2011
• Date of issue
  June 2011

History

• Received
  04 Feb 2011
• Accepted
  15 Feb 2011