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Metabolic syndrome in rheumatological diseases
Autoimmunity Reviews 8 (2009) 415–419
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Metabolic syndrome in rheumatological diseases Rosa Maria Rodrigues Pereira ⁎, Jozélio Freire de Carvalho, Eloísa Bonfá Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Article history: Received 3 January 2009 Accepted 7 January 2009 Available online 23 January 2009 Keywords: Metabolic syndrome Rheumatoid arthritis Systemic lupus erythematosus Gout Osteoarthritis Ankylosing spondylitis Sjögren's syndrome
a b s t r a c t Metabolic syndrome is characterized by a combination of various cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component. Herein, the authors review the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ankylosing spondylitis. The prevalence of metabolic syndrome in these disorders varies from 14% to 62.8%. The great majority of these studies demonstrated that this frequency was higher in rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases seems to influence the risk of developing metabolic syndrome. © 2009 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . 2. Metabolic syndrome criteria . . . . . . . . . . . . . 3. Gout and metabolic syndrome . . . . . . . . . . . . 4. Osteoarthritis and metabolic syndrome . . . . . . . . 5. Systemic lupus erythematosus and metabolic syndrome 6. Rheumatoid arthritis and metabolic syndrome . . . . 7. Sjögren's syndrome and metabolic syndrome . . . . . 8. Ankylosing spondylitis and metabolic syndrome . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Patients with rheumatological diseases are at an increased risk of mortality, and coronary disease is the leading cause of ⁎ Corresponding author. Faculdade de Medicina da Universidade de São Paulo, Disciplina de Reumatologia, Av. Dr. Arnaldo 455, 30 andar, Sala 3105, São Paulo-SP-Brazil, ZIPCODE: 01246-903, Brazil. Fax: +55 11 30617490. E-mail address: [email protected] (R.M.R. Pereira). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.01.001
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death among such patients [1–3]. Among the various rheumatological diseases, gout, osteoarthritis and immunoinflammatory diseases have been associated with an increase in the prevalence of cardiovascular disease [1,4]. Studies have demonstrated that atherosclerosis is accelerated in patients with rheumatological diseases, although the causal factors have yet to be completely elucidated [3]. Although traditional cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) have been implicated in the
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physiopathology of atherosclerosis, such features do not appear to fully explain the increased cardiovascular risk increased in this population of patients [5,6]. Metabolic syndrome is characterized by a combination of various risk factors that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component [7]. Various studies have shown that the pathogenesis of metabolic syndrome involves an inflammatory process. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), reduce the activity of insulin, thereby promoting insulin resistance [8]. Inflammation has also been associated with obesity, as well as with elevated levels and triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol [9]. Although metabolic syndrome has only recently been recognized, it has taken on great importance in the context of atherosclerosis. The syndrome is composed of various risk factors associated with the atherosclerotic process, linked together not only by their capacity to promote the same outcome but also by their tendency to aggregate in the same individual. 2. Metabolic syndrome criteria The strong association between metabolic syndrome and the incidence of atherosclerosis prompted attempts to characterize the syndrome and, consequently, to define relevant criteria for its diagnosis. To that end, the World Health Organization (WHO) defined criteria outlining that, in order to be diagnosed with metabolic syndrome, an individual should present insulin resistance, plus two or more of the following parameters: ➢ arterial blood pressure ≥140/90 mm Hg ➢ plasma triglycerides ≥150 mg/dL and HDL cholesterol b35 mg/dL (for men) or b39 mg/dL (for women) ➢ obesity, defined as a high waist/hip ratio (N0.9 for men and N0.85 for women) or a body mass index (BMI) N30 kg/m2 ➢ urinary excretion of albumin N20 µg/min [10,11]. However, this method proved not viable for the screening of individuals at higher risk, because the various methods to quantify insulin resistance are complex and costly. The most sensitive method, considered the gold standard, is the hyperinsulinemic–euglycemic clamp, which consists of the constant infusion of insulin, maintaining insulinemia at 100 mU/L. The quantity of glucose administered in order to maintain normal levels of glycemia is inversely proportional to the degree of insulin resistance. A similar method is the insulin suppression test, in which the risks and costs are lower, since, although the test is the same, endogenous insulin is suppressed. Another method involves the application of a mathematical model in order to determine the minimum dose of insulin required to elicit a response (the dose–response relationship) in patients with intravenous glucose overload. Although this method is simpler than are the other methods, it has certain limitations. Epidemiological studies, however, have employed measurement of fasting insulin or of insulin levels at 2 h after oral glucose overload, as well as, more recently, the homeostasis model assessment, which is derived from the fasting levels of glycemia and insulinemia [11].
In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) published a clinical description of metabolic syndrome, defining it as the presentation of three or more of the following factors: ➢ abdominal obesity, characterized as waist circumference N102 cm (for men) or N88 cm (for women) ➢ triglyceride level ≥150 mg/dL ➢ HDL cholesterol level b40 mg/dL (for men) and b50 mg/dL (for women) ➢ arterial blood pressure ≥130/85 mm Hg ➢ fasting glycemia ≥110 mg/dL [12]. Here, we address the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ankylosing spondylitis. 3. Gout and metabolic syndrome Gout is a type of inflammatory arthritis that is characterized by hyperuricemia. It is well known that gout is associated with hypertension, hyperglycemia, obesity and dyslipidemia. Rho et al. employed the NCEP/ATP III criteria to evaluate 168 patients with gout and found the age-adjusted prevalence of metabolic syndrome to be 43.6%, significantly greater than the 5.2% observed in the control population [13]. Studying a population of 8807 participants over 20 years of age, Choi et al. found that, when the NCEP/ATPIII criteria were employed, the prevalence of metabolic syndrome was 62.8% among the individuals with gout, compared with 25.4% among those without it. The authors observed an increased risk of metabolic syndrome, which was 3.05 (95% CI: 2.01–4.61) after being adjusted for age and gender [14] (Table 1). In a recent study involving 12,179 men stratified by age and compared with a control population, Chen et al. evaluated the components of metabolic syndrome associated with gout. The authors found that the incidence of overweight, type 2 diabetes mellitus and hypertriglyceridemia was significantly higher in the population with gout than among the controls, regardless of age group. It is of note that the authors found the risk of type 2 diabetes mellitus to be greater for the younger portion of the population with gout (those 19–44 years of age). The frequency of hypercholesterolemia was also shown to be higher among the individuals with gout than among the controls, except among those in the highest age group (≥65 years of age). However, the prevalence of arterial hypertension was higher only among those in the highest age group [15]. 4. Osteoarthritis and metabolic syndrome There has been only one study in which the prevalence of metabolic syndrome was studied in patients with osteoarthritis. The authors of that study, which was published in the Russian literature, evaluated a population of 1350 individuals diagnosed with osteoarthritis and demonstrated that the frequency of metabolic syndrome among those individuals was 62.56%. In that study, the individuals with metabolic syndrome more often presented cardiovascular disease, gastrointestinal disease, renal disease, thyroid disease and diabetes mellitus, as well as the complications of those diseases. Of the 1350 individuals with osteoarthritis, 270 (20%) were
R.M.R. Pereira et al. / Autoimmunity Reviews 8 (2009) 415–419
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Table 1 Frequency of metabolic syndrome in the various rheumatological conditions studied Disease
WHO criteria
NCEP ATPIII criteria
Other criteria
Reference
Gout
– – – – 32% –
43.6% 62.8% – 18% 29.4% 20% 20% 16% 19% 41% 31–42% – 45.8% 34.9%
– – 62.56% – – – – – – – – 58% – –
Rho et al., 2005 [13] Choi et al., 2007 [14] Korochina and Bagirova 2005 [16] El Magadmi et al., 2006 [18] Chung et al., 2007 [19] Azevedo et al., 2007 [20] Sabio et al., 2008 [21] Bultink et al., 2008 [22] Dessein et al., 2006 [23] Karvounaris et al., 2007 [24] Chung et al., 2008 [26] Ramos-Casals et al., 2007 [27] Malesci et al., 2007 [28] Sidiropoulos et al., 2008 [25]
Osteoarthritis Systemic lupus erythematosus
Rheumatoid arthritis
Sjögren's syndrome Ankylosing spondylitis
14% – 30–42% – – –
considered incapacitated, the osteoarthritis being accompanied by metabolic syndrome in 243 (90.17%) of those 270 [16] (Table 1). Engström et al. evaluated the relationship between metabolic syndrome and osteoarthritis in 5171 individuals. The authors found that 120 had osteoarthritis of the hip and 89 had osteoarthritis of the knees. After adjusting for age, gender, smoking, physical activity and level of C-reactive protein, the authors found that the presence of metabolic syndrome correlated significantly with osteoarthritis of the knees (relative risk: 2.1, 95% CI: 1.3–3.3). However, after adjustment for BMI, this relationship ceased to exist. The authors concluded that the increased frequency of knee osteoarthritis in patients with metabolic syndrome was attributable to the increase in BMI [17].
4.2%, p b 0.001). In addition, the number of metabolic syndrome criteria met, as well as the frequency of cardiovascular disease, was significantly higher in the lupus patients than in the controls. Furthermore, the levels of inflammatory markers were higher among the patients with metabolic syndrome than among those without. In the multivariate analysis, level of education, triglyceride level, HDL level, level of complement C3 and use of hydroxychloroquine were independently associated with metabolic syndrome [21] (Table 1). Evaluating 121 Dutch women with systemic lupus erythematosus, Bultink et al. applied the NCEP/ATPIII criteria and found the prevalence of metabolic syndrome to be 16%, comparable to that reported for the general population of Holland. The lupus patients with metabolic syndrome presented a history of cardiovascular events more often than did those without metabolic syndrome [22] (Table 1).
5. Systemic lupus erythematosus and metabolic syndrome 6. Rheumatoid arthritis and metabolic syndrome In a study involving 44 patients with systemic lupus erythematosus and applying the NCEP/ATPIII criteria, 8 (18%) were diagnosed with metabolic syndrome [18]. However, another study employed the WHO criteria and the NCEP/ ATPIII criteria to evaluate a larger sample of patients with systemic lupus erythematosus (n = 102) in comparison with a group of age- and gender-matched controls (n = 101). In that study, the prevalence of metabolic syndrome was found to be significantly higher in the patients than in the controls (32.4% vs. 10.9%) when the WHO criteria were applied, although this difference did not achieve statistical significance when the NCEP/ATPIII criteria were applied (29.4% vs. 19.8%). The authors found that the presence of metabolic syndrome correlated with high levels of C-reactive protein, although not with the activity score or with lupus chronicity [19] (Table 1). In a study conducted in Brazil, the NCEP/ATPIII criteria were applied in patients with lupus, who were found to present a higher prevalence of metabolic syndrome and of its individual components than did the controls (20% vs. 5.4%, p = 0.03). The lupus disease duration was not found to be associated with the prevalence of metabolic syndrome [20] (Table 1). In a Spanish study involving 160 lupus patients and 245 healthy controls, the frequency of metabolic syndrome was found to be similar between the two groups (20% vs. 13%, p = 0.083). However, evaluating only those of 40 years of age or less, the authors found a significant difference (15.8% vs.
According to one study, the prevalence of metabolic syndrome among patients with rheumatoid arthritis is 14% when diagnosed according to the WHO criteria and 19% when the NCEP/ATPIII criteria are applied. Carotid ultrasound evaluation revealed that metabolic syndrome was associated with carotid intima-media thickness only in the patients presenting metabolic syndrome according to the WHO criteria [23]. Karvounaris et al. studying a group of 200 patients with rheumatoid arthritis (mean age, 63 years) in comparison with a group of 400 age- and gender-matched individuals without rheumatoid arthritis, found that the prevalence of metabolic syndrome among the patients was high (44%), albeit comparable to that observed for the control population (41%). In the logistic regression analysis, the risk of developing moderate-to-intense rheumatoid arthritis was found to be higher for patients with metabolic syndrome than for those without (odds ratio: 9.2, 95% CI: 1.49–57), regardless of the treatment given [24] (Table 1). The same authors demonstrated that, in patients with rheumatoid arthritis and metabolic syndrome, three months of treatment with anti-TNF resulted in reduced insulin resistance [25]. Chung et al. studied 154 patients with rheumatoid arthritis and compared them with a control group. The authors applied the WHO criteria as well as the NCEP ATPIII criteria and found that the prevalence of metabolic syndrome was higher among
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the patients, regardless of the criteria applied. It is of note that the prevalence of this syndrome was higher among the patients having had rheumatoid arthritis for a longer time than among those in the initial phases of the disease (42% vs. 31%). The increased risk of present coronary calcification was found to be independent of age and gender [26] (Table 1). In summary, the high prevalence of metabolic syndrome in rheumatoid arthritis is associated with disease activity and inflammatory markers. 7. Sjögren's syndrome and metabolic syndrome Ramos-Casals et al. studying 254 patients with primary Sjögren's syndrome, showed that the frequency of hypercholesterolemia, hypertriglyceridemia, diabetes mellitus or hyperuricemia was 58%. It is noteworthy that the presence of hypercholesterolemia was accompanied by a lower frequency of immunological markers (anti-Ro, anti-La, complement C3 and complement C4). Nevertheless, hypertriglyceridemia and diabetes mellitus were found to be associated with a high prevalence of extraglandular findings (hepatic and renal, as well as vasculitis) [27] (Table 1). 8. Ankylosing spondylitis and metabolic syndrome In a study involving 24 patients with ankylosing spondylitis, the prevalence of metabolic syndrome, according to the NCEP/ ATPIII criteria, was found to be considerably higher than that seen in the controls (45.8% vs. 10.5%) [28]. In another study, involving 63 patients with spondylitis receiving anti-TNF therapy, the prevalence of metabolic syndrome (NCEP/ATPIII criteria) was also higher among the patients than among the controls (34.9% vs. 19%), and metabolic syndrome was associated with higher disease activity, as assessed using the Bath Ankylosing Spondylitis Disease Activity Index [25] (Table 1). 9. Conclusion There are few studies in the literature evaluating metabolic syndrome in rheumatological diseases, and only six such diseases were addressed in this review. The prevalence was found to range from 14% to 62.8%, and various classification criteria have been applied. The great majority of the studies analyzed demonstrated that the frequency of metabolic syndrome was higher in the patients with rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases influences the risk of developing metabolic syndrome. Take-home messages • Metabolic syndrome is associated with an increased cardiovascular risk and has been studied in some rheumatic conditions (gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and ankylosing spondylitis). • The prevalence of metabolic syndrome is higher in rheumatological diseases (14% to 62.8%) than control population. • Diseases itself and treatment may be implicated in the risk of appearance of metabolic syndrome.
Acknowledgments This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico [305691/2006-6 to R.M.R.P., 305468/2006-5 to E.B.] and Federico Foundation to E.B. References [1] Abou-Raya A, Abou-Raya S. Inflammation: a pivotal link between autoimmune diseases and atherosclerosis. Autoimmun Rev 2006;5:331–7. [2] Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriouslypredictive markers, socioeconomic status and comorbidity. J Rheumatol 1986;13:841–5. [3] Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger Jr TA, JansenMcWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408–15. [4] Krishnan E. Gout and coronary artery disease: epidemiologic clues. Curr Rheumatol Rep 2008;10:249–55. [5] Kiani AN, Magder L, Petri M. Coronary calcium in systemic lupus erythematosus is associated with traditional cardiovascular risk factors, but not with disease activity. J Rheumatol 2008;35:1300–6. [6] Chung CP, Oeser A, Raggi P, Gebretsadik T, Shintani AK, Sokka T, et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum 2005;52:3045–53. [7] Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:1546–51. [8] Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H. Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1998;18:1199–202. [9] Piché ME, Lemieux S, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J. Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol 2005;96:92–7. [10] Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 2002;156:1070–7. [11] 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;110:803–9. [12] Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [13] Rho YH, Choi SJ, Lee YH, Ji JD, Choi KM, Baik SH, et al. The prevalence of metabolic syndrome in patients with gout: a multicenter study. J Korean Med Sci 2005;20:1029–33. [14] Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2007;57:109–15. [15] Chen SY, Chen CI, Shen MI. Manifestations of metabolic syndrome associated with male gout in different age strata. Clin Rheumatol 2007;26:1453–7. [16] Korochina IE, Bagirova GG. Metabolic syndrome and a course of osteoarthrosis. Ter Arkh 2007;79:13–20. [17] Engström G, Gerhardsson DE, Verdier M, Rollof J, Nilsson PM, Lohmander LS. C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study. Osteoarthr Cartil 2008;28 [Electronic publication]. [18] EI Magadmi M, Ahmad Y, Turkie W, Yates AP, Sheikh N, Bernstein RM, et al. Hyperinsulinemia, insulin resistance, and circulating oxidized low density lipoprotein in women with systemic lupus erythematosus. J Rheumatol 2006;33:50–6. [19] Chung CP, Avalos I, Oeser A, Gebretsadik T, Shintani A, Raggi P, et al. High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007;66:208–14. [20] Azevedo GD, Gadelha RG, Vilar MJ. Metabolic syndrome in systemic lupus erythematosus: lower prevalence in Brazil than in the USA. Ann Rheum Dis 2007;66:1542. [21] Sabio J, Zamora-Pasadas M, Jiménez-Jáimez J, Albadalejo F, Vargas-Hitos J, Rodríguez Del Aguila M, et al. Metabolic syndrome in patients with systemic lupus erythematosus from Southern Spain. Lupus 2008;17:849–59.
R.M.R. Pereira et al. / Autoimmunity Reviews 8 (2009) 415–419 [22] Bultink IE, Turkstra F, Diamant M, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for the metabolic syndrome in women with systemic lupus erythematosus. Clin Exp Rheumatol 2008;26:32–8 2008. [23] Dessein PH, Tobias M, Veller MG. Metabolic syndrome and subclinical atherosclerosis in rheumatoid arthritis. J Rheumatol 2006;33:2425–32. [24] 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;66:28–33. [25] Sidiropoulos PI, Karvounaris SA, Boumpas DT. Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications. Arthritis Res Ther 2008;10:207.
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[26] 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;196:756–63. [27] Ramos-Casals M, Brito-Zerón P, Sisó A, Vargas A, Ros E, Bove A, et al. High prevalence of serum metabolic alterations in primary Sjögren's syndrome: influence on clinical and immunological expression. J Rheumatol 2007;34:54–61. [28] Malesci D, Niglio A, Mennillo GA, Buono R, Valentini G, La Montagna G. High prevalence of metabolic syndrome in patients with ankylosing spondylitis. Clin Rheumatol 2007;26:710–4.
Prophylaxis and treatment of experimental autoimmune encephalomyelitis Modulation of immune system is a tentative form to treat or to prevent autoimmune disorders. In this line, Kobayashi et al. (Clin Immunol 2008;129:69-79) have developed a peptide called bifunctional peptide inhibitor (BPI) that target and inhibit the immunological synapse. The authors have conjugated this peptide with myelin proteolipid protein (PLP) creating the PLP-BPI complex. They have injected PLP-BPI derivates to experimental autoimmune encephalomyelitis animals in which they could prevent neurological damage progression. In addition, the levels of interleukin-17, a proinflammatory cytokine associated with multiple sclerosis, were lower in mice treated with this novel peptide. In summary, the present study showes that PLP-BPI derivates are able to prevent and to treat experimental autoimmune encephalomyelitis.
Interleukin-20 and lupus nephritis Various cytokines, such as interleukin-10, have been implicated in lupus nephritis pathophysiology. In this line, Li et al. (Clin Immunol 2008;129:277-85) have evaluated the expression of interleukin-20, a member of the interleukin-10 family, and its receptor in the mesangial cells of two lupus animal models (NZB/W and DBA/W mice). The authors observed an increased expression of interleukin-20 in mesangial cell of NZB/W. Moreover, the incubation of mesangial cells with interleukin-20 revealed an overexpression of the followings: transcripts of CCL2 (MCP-1), CXCL10 (IP-10), interleukin-6, iNOS, and ROS. All these substances are involved in the physiopathology of lupus glomerulonephritis. This article alludes to interleukin-20 as a novel player in the pathogenesis of lupus nephritis.
Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus In this study, a comprehensive set of single-nucleotide polymorphism (SNPs) and length polymorphisms in interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. Sigurdsson S. et al. (Human Molecular Genetics 2008; 17: 872-81). The authors found 16 SNPs and two length polymorphisms that display association with SLE (p b0.0005), OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3’ of IRF5, and a novel CGGGG insertion-depletion (indel)polymorphism located 64 bp upstream of the first untranslanted exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays the authors show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay they show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of CGGG indel. The same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Metabolic syndrome in rheumatological diseases Rosa Maria Rodrigues Pereira ⁎, Jozélio Freire de Carvalho, Eloísa Bonfá Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 3 January 2009 Accepted 7 January 2009 Available online 23 January 2009 Keywords: Metabolic syndrome Rheumatoid arthritis Systemic lupus erythematosus Gout Osteoarthritis Ankylosing spondylitis Sjögren's syndrome
a b s t r a c t Metabolic syndrome is characterized by a combination of various cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component. Herein, the authors review the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ankylosing spondylitis. The prevalence of metabolic syndrome in these disorders varies from 14% to 62.8%. The great majority of these studies demonstrated that this frequency was higher in rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases seems to influence the risk of developing metabolic syndrome. © 2009 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . 2. Metabolic syndrome criteria . . . . . . . . . . . . . 3. Gout and metabolic syndrome . . . . . . . . . . . . 4. Osteoarthritis and metabolic syndrome . . . . . . . . 5. Systemic lupus erythematosus and metabolic syndrome 6. Rheumatoid arthritis and metabolic syndrome . . . . 7. Sjögren's syndrome and metabolic syndrome . . . . . 8. Ankylosing spondylitis and metabolic syndrome . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Patients with rheumatological diseases are at an increased risk of mortality, and coronary disease is the leading cause of ⁎ Corresponding author. Faculdade de Medicina da Universidade de São Paulo, Disciplina de Reumatologia, Av. Dr. Arnaldo 455, 30 andar, Sala 3105, São Paulo-SP-Brazil, ZIPCODE: 01246-903, Brazil. Fax: +55 11 30617490. E-mail address: [email protected] (R.M.R. Pereira). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.01.001
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death among such patients [1–3]. Among the various rheumatological diseases, gout, osteoarthritis and immunoinflammatory diseases have been associated with an increase in the prevalence of cardiovascular disease [1,4]. Studies have demonstrated that atherosclerosis is accelerated in patients with rheumatological diseases, although the causal factors have yet to be completely elucidated [3]. Although traditional cardiovascular risk factors (age, gender, smoking, hypertension and dyslipidemia) have been implicated in the
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physiopathology of atherosclerosis, such features do not appear to fully explain the increased cardiovascular risk increased in this population of patients [5,6]. Metabolic syndrome is characterized by a combination of various risk factors that imply additional cardiovascular morbidity that is greater than the sum of the risks associated with each individual component [7]. Various studies have shown that the pathogenesis of metabolic syndrome involves an inflammatory process. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), reduce the activity of insulin, thereby promoting insulin resistance [8]. Inflammation has also been associated with obesity, as well as with elevated levels and triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol [9]. Although metabolic syndrome has only recently been recognized, it has taken on great importance in the context of atherosclerosis. The syndrome is composed of various risk factors associated with the atherosclerotic process, linked together not only by their capacity to promote the same outcome but also by their tendency to aggregate in the same individual. 2. Metabolic syndrome criteria The strong association between metabolic syndrome and the incidence of atherosclerosis prompted attempts to characterize the syndrome and, consequently, to define relevant criteria for its diagnosis. To that end, the World Health Organization (WHO) defined criteria outlining that, in order to be diagnosed with metabolic syndrome, an individual should present insulin resistance, plus two or more of the following parameters: ➢ arterial blood pressure ≥140/90 mm Hg ➢ plasma triglycerides ≥150 mg/dL and HDL cholesterol b35 mg/dL (for men) or b39 mg/dL (for women) ➢ obesity, defined as a high waist/hip ratio (N0.9 for men and N0.85 for women) or a body mass index (BMI) N30 kg/m2 ➢ urinary excretion of albumin N20 µg/min [10,11]. However, this method proved not viable for the screening of individuals at higher risk, because the various methods to quantify insulin resistance are complex and costly. The most sensitive method, considered the gold standard, is the hyperinsulinemic–euglycemic clamp, which consists of the constant infusion of insulin, maintaining insulinemia at 100 mU/L. The quantity of glucose administered in order to maintain normal levels of glycemia is inversely proportional to the degree of insulin resistance. A similar method is the insulin suppression test, in which the risks and costs are lower, since, although the test is the same, endogenous insulin is suppressed. Another method involves the application of a mathematical model in order to determine the minimum dose of insulin required to elicit a response (the dose–response relationship) in patients with intravenous glucose overload. Although this method is simpler than are the other methods, it has certain limitations. Epidemiological studies, however, have employed measurement of fasting insulin or of insulin levels at 2 h after oral glucose overload, as well as, more recently, the homeostasis model assessment, which is derived from the fasting levels of glycemia and insulinemia [11].
In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) published a clinical description of metabolic syndrome, defining it as the presentation of three or more of the following factors: ➢ abdominal obesity, characterized as waist circumference N102 cm (for men) or N88 cm (for women) ➢ triglyceride level ≥150 mg/dL ➢ HDL cholesterol level b40 mg/dL (for men) and b50 mg/dL (for women) ➢ arterial blood pressure ≥130/85 mm Hg ➢ fasting glycemia ≥110 mg/dL [12]. Here, we address the rheumatological diseases in which metabolic syndrome has been studied: gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ankylosing spondylitis. 3. Gout and metabolic syndrome Gout is a type of inflammatory arthritis that is characterized by hyperuricemia. It is well known that gout is associated with hypertension, hyperglycemia, obesity and dyslipidemia. Rho et al. employed the NCEP/ATP III criteria to evaluate 168 patients with gout and found the age-adjusted prevalence of metabolic syndrome to be 43.6%, significantly greater than the 5.2% observed in the control population [13]. Studying a population of 8807 participants over 20 years of age, Choi et al. found that, when the NCEP/ATPIII criteria were employed, the prevalence of metabolic syndrome was 62.8% among the individuals with gout, compared with 25.4% among those without it. The authors observed an increased risk of metabolic syndrome, which was 3.05 (95% CI: 2.01–4.61) after being adjusted for age and gender [14] (Table 1). In a recent study involving 12,179 men stratified by age and compared with a control population, Chen et al. evaluated the components of metabolic syndrome associated with gout. The authors found that the incidence of overweight, type 2 diabetes mellitus and hypertriglyceridemia was significantly higher in the population with gout than among the controls, regardless of age group. It is of note that the authors found the risk of type 2 diabetes mellitus to be greater for the younger portion of the population with gout (those 19–44 years of age). The frequency of hypercholesterolemia was also shown to be higher among the individuals with gout than among the controls, except among those in the highest age group (≥65 years of age). However, the prevalence of arterial hypertension was higher only among those in the highest age group [15]. 4. Osteoarthritis and metabolic syndrome There has been only one study in which the prevalence of metabolic syndrome was studied in patients with osteoarthritis. The authors of that study, which was published in the Russian literature, evaluated a population of 1350 individuals diagnosed with osteoarthritis and demonstrated that the frequency of metabolic syndrome among those individuals was 62.56%. In that study, the individuals with metabolic syndrome more often presented cardiovascular disease, gastrointestinal disease, renal disease, thyroid disease and diabetes mellitus, as well as the complications of those diseases. Of the 1350 individuals with osteoarthritis, 270 (20%) were
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Table 1 Frequency of metabolic syndrome in the various rheumatological conditions studied Disease
WHO criteria
NCEP ATPIII criteria
Other criteria
Reference
Gout
– – – – 32% –
43.6% 62.8% – 18% 29.4% 20% 20% 16% 19% 41% 31–42% – 45.8% 34.9%
– – 62.56% – – – – – – – – 58% – –
Rho et al., 2005 [13] Choi et al., 2007 [14] Korochina and Bagirova 2005 [16] El Magadmi et al., 2006 [18] Chung et al., 2007 [19] Azevedo et al., 2007 [20] Sabio et al., 2008 [21] Bultink et al., 2008 [22] Dessein et al., 2006 [23] Karvounaris et al., 2007 [24] Chung et al., 2008 [26] Ramos-Casals et al., 2007 [27] Malesci et al., 2007 [28] Sidiropoulos et al., 2008 [25]
Osteoarthritis Systemic lupus erythematosus
Rheumatoid arthritis
Sjögren's syndrome Ankylosing spondylitis
14% – 30–42% – – –
considered incapacitated, the osteoarthritis being accompanied by metabolic syndrome in 243 (90.17%) of those 270 [16] (Table 1). Engström et al. evaluated the relationship between metabolic syndrome and osteoarthritis in 5171 individuals. The authors found that 120 had osteoarthritis of the hip and 89 had osteoarthritis of the knees. After adjusting for age, gender, smoking, physical activity and level of C-reactive protein, the authors found that the presence of metabolic syndrome correlated significantly with osteoarthritis of the knees (relative risk: 2.1, 95% CI: 1.3–3.3). However, after adjustment for BMI, this relationship ceased to exist. The authors concluded that the increased frequency of knee osteoarthritis in patients with metabolic syndrome was attributable to the increase in BMI [17].
4.2%, p b 0.001). In addition, the number of metabolic syndrome criteria met, as well as the frequency of cardiovascular disease, was significantly higher in the lupus patients than in the controls. Furthermore, the levels of inflammatory markers were higher among the patients with metabolic syndrome than among those without. In the multivariate analysis, level of education, triglyceride level, HDL level, level of complement C3 and use of hydroxychloroquine were independently associated with metabolic syndrome [21] (Table 1). Evaluating 121 Dutch women with systemic lupus erythematosus, Bultink et al. applied the NCEP/ATPIII criteria and found the prevalence of metabolic syndrome to be 16%, comparable to that reported for the general population of Holland. The lupus patients with metabolic syndrome presented a history of cardiovascular events more often than did those without metabolic syndrome [22] (Table 1).
5. Systemic lupus erythematosus and metabolic syndrome 6. Rheumatoid arthritis and metabolic syndrome In a study involving 44 patients with systemic lupus erythematosus and applying the NCEP/ATPIII criteria, 8 (18%) were diagnosed with metabolic syndrome [18]. However, another study employed the WHO criteria and the NCEP/ ATPIII criteria to evaluate a larger sample of patients with systemic lupus erythematosus (n = 102) in comparison with a group of age- and gender-matched controls (n = 101). In that study, the prevalence of metabolic syndrome was found to be significantly higher in the patients than in the controls (32.4% vs. 10.9%) when the WHO criteria were applied, although this difference did not achieve statistical significance when the NCEP/ATPIII criteria were applied (29.4% vs. 19.8%). The authors found that the presence of metabolic syndrome correlated with high levels of C-reactive protein, although not with the activity score or with lupus chronicity [19] (Table 1). In a study conducted in Brazil, the NCEP/ATPIII criteria were applied in patients with lupus, who were found to present a higher prevalence of metabolic syndrome and of its individual components than did the controls (20% vs. 5.4%, p = 0.03). The lupus disease duration was not found to be associated with the prevalence of metabolic syndrome [20] (Table 1). In a Spanish study involving 160 lupus patients and 245 healthy controls, the frequency of metabolic syndrome was found to be similar between the two groups (20% vs. 13%, p = 0.083). However, evaluating only those of 40 years of age or less, the authors found a significant difference (15.8% vs.
According to one study, the prevalence of metabolic syndrome among patients with rheumatoid arthritis is 14% when diagnosed according to the WHO criteria and 19% when the NCEP/ATPIII criteria are applied. Carotid ultrasound evaluation revealed that metabolic syndrome was associated with carotid intima-media thickness only in the patients presenting metabolic syndrome according to the WHO criteria [23]. Karvounaris et al. studying a group of 200 patients with rheumatoid arthritis (mean age, 63 years) in comparison with a group of 400 age- and gender-matched individuals without rheumatoid arthritis, found that the prevalence of metabolic syndrome among the patients was high (44%), albeit comparable to that observed for the control population (41%). In the logistic regression analysis, the risk of developing moderate-to-intense rheumatoid arthritis was found to be higher for patients with metabolic syndrome than for those without (odds ratio: 9.2, 95% CI: 1.49–57), regardless of the treatment given [24] (Table 1). The same authors demonstrated that, in patients with rheumatoid arthritis and metabolic syndrome, three months of treatment with anti-TNF resulted in reduced insulin resistance [25]. Chung et al. studied 154 patients with rheumatoid arthritis and compared them with a control group. The authors applied the WHO criteria as well as the NCEP ATPIII criteria and found that the prevalence of metabolic syndrome was higher among
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the patients, regardless of the criteria applied. It is of note that the prevalence of this syndrome was higher among the patients having had rheumatoid arthritis for a longer time than among those in the initial phases of the disease (42% vs. 31%). The increased risk of present coronary calcification was found to be independent of age and gender [26] (Table 1). In summary, the high prevalence of metabolic syndrome in rheumatoid arthritis is associated with disease activity and inflammatory markers. 7. Sjögren's syndrome and metabolic syndrome Ramos-Casals et al. studying 254 patients with primary Sjögren's syndrome, showed that the frequency of hypercholesterolemia, hypertriglyceridemia, diabetes mellitus or hyperuricemia was 58%. It is noteworthy that the presence of hypercholesterolemia was accompanied by a lower frequency of immunological markers (anti-Ro, anti-La, complement C3 and complement C4). Nevertheless, hypertriglyceridemia and diabetes mellitus were found to be associated with a high prevalence of extraglandular findings (hepatic and renal, as well as vasculitis) [27] (Table 1). 8. Ankylosing spondylitis and metabolic syndrome In a study involving 24 patients with ankylosing spondylitis, the prevalence of metabolic syndrome, according to the NCEP/ ATPIII criteria, was found to be considerably higher than that seen in the controls (45.8% vs. 10.5%) [28]. In another study, involving 63 patients with spondylitis receiving anti-TNF therapy, the prevalence of metabolic syndrome (NCEP/ATPIII criteria) was also higher among the patients than among the controls (34.9% vs. 19%), and metabolic syndrome was associated with higher disease activity, as assessed using the Bath Ankylosing Spondylitis Disease Activity Index [25] (Table 1). 9. Conclusion There are few studies in the literature evaluating metabolic syndrome in rheumatological diseases, and only six such diseases were addressed in this review. The prevalence was found to range from 14% to 62.8%, and various classification criteria have been applied. The great majority of the studies analyzed demonstrated that the frequency of metabolic syndrome was higher in the patients with rheumatological diseases than in the control populations, suggesting that either the presence or the treatment of those diseases influences the risk of developing metabolic syndrome. Take-home messages • Metabolic syndrome is associated with an increased cardiovascular risk and has been studied in some rheumatic conditions (gout, osteoarthritis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and ankylosing spondylitis). • The prevalence of metabolic syndrome is higher in rheumatological diseases (14% to 62.8%) than control population. • Diseases itself and treatment may be implicated in the risk of appearance of metabolic syndrome.
Acknowledgments This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico [305691/2006-6 to R.M.R.P., 305468/2006-5 to E.B.] and Federico Foundation to E.B. References [1] Abou-Raya A, Abou-Raya S. Inflammation: a pivotal link between autoimmune diseases and atherosclerosis. Autoimmun Rev 2006;5:331–7. [2] Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriouslypredictive markers, socioeconomic status and comorbidity. J Rheumatol 1986;13:841–5. [3] Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger Jr TA, JansenMcWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408–15. [4] Krishnan E. Gout and coronary artery disease: epidemiologic clues. Curr Rheumatol Rep 2008;10:249–55. [5] Kiani AN, Magder L, Petri M. Coronary calcium in systemic lupus erythematosus is associated with traditional cardiovascular risk factors, but not with disease activity. J Rheumatol 2008;35:1300–6. [6] Chung CP, Oeser A, Raggi P, Gebretsadik T, Shintani AK, Sokka T, et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum 2005;52:3045–53. [7] Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation 2003;108:1546–51. [8] Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H. Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1998;18:1199–202. [9] Piché ME, Lemieux S, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J. Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol 2005;96:92–7. [10] Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 2002;156:1070–7. [11] 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;110:803–9. [12] Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [13] Rho YH, Choi SJ, Lee YH, Ji JD, Choi KM, Baik SH, et al. The prevalence of metabolic syndrome in patients with gout: a multicenter study. J Korean Med Sci 2005;20:1029–33. [14] Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2007;57:109–15. [15] Chen SY, Chen CI, Shen MI. Manifestations of metabolic syndrome associated with male gout in different age strata. Clin Rheumatol 2007;26:1453–7. [16] Korochina IE, Bagirova GG. Metabolic syndrome and a course of osteoarthrosis. Ter Arkh 2007;79:13–20. [17] Engström G, Gerhardsson DE, Verdier M, Rollof J, Nilsson PM, Lohmander LS. C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study. Osteoarthr Cartil 2008;28 [Electronic publication]. [18] EI Magadmi M, Ahmad Y, Turkie W, Yates AP, Sheikh N, Bernstein RM, et al. Hyperinsulinemia, insulin resistance, and circulating oxidized low density lipoprotein in women with systemic lupus erythematosus. J Rheumatol 2006;33:50–6. [19] Chung CP, Avalos I, Oeser A, Gebretsadik T, Shintani A, Raggi P, et al. High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007;66:208–14. [20] Azevedo GD, Gadelha RG, Vilar MJ. Metabolic syndrome in systemic lupus erythematosus: lower prevalence in Brazil than in the USA. Ann Rheum Dis 2007;66:1542. [21] Sabio J, Zamora-Pasadas M, Jiménez-Jáimez J, Albadalejo F, Vargas-Hitos J, Rodríguez Del Aguila M, et al. Metabolic syndrome in patients with systemic lupus erythematosus from Southern Spain. Lupus 2008;17:849–59.
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Prophylaxis and treatment of experimental autoimmune encephalomyelitis Modulation of immune system is a tentative form to treat or to prevent autoimmune disorders. In this line, Kobayashi et al. (Clin Immunol 2008;129:69-79) have developed a peptide called bifunctional peptide inhibitor (BPI) that target and inhibit the immunological synapse. The authors have conjugated this peptide with myelin proteolipid protein (PLP) creating the PLP-BPI complex. They have injected PLP-BPI derivates to experimental autoimmune encephalomyelitis animals in which they could prevent neurological damage progression. In addition, the levels of interleukin-17, a proinflammatory cytokine associated with multiple sclerosis, were lower in mice treated with this novel peptide. In summary, the present study showes that PLP-BPI derivates are able to prevent and to treat experimental autoimmune encephalomyelitis.
Interleukin-20 and lupus nephritis Various cytokines, such as interleukin-10, have been implicated in lupus nephritis pathophysiology. In this line, Li et al. (Clin Immunol 2008;129:277-85) have evaluated the expression of interleukin-20, a member of the interleukin-10 family, and its receptor in the mesangial cells of two lupus animal models (NZB/W and DBA/W mice). The authors observed an increased expression of interleukin-20 in mesangial cell of NZB/W. Moreover, the incubation of mesangial cells with interleukin-20 revealed an overexpression of the followings: transcripts of CCL2 (MCP-1), CXCL10 (IP-10), interleukin-6, iNOS, and ROS. All these substances are involved in the physiopathology of lupus glomerulonephritis. This article alludes to interleukin-20 as a novel player in the pathogenesis of lupus nephritis.
Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus In this study, a comprehensive set of single-nucleotide polymorphism (SNPs) and length polymorphisms in interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. Sigurdsson S. et al. (Human Molecular Genetics 2008; 17: 872-81). The authors found 16 SNPs and two length polymorphisms that display association with SLE (p b0.0005), OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3’ of IRF5, and a novel CGGGG insertion-depletion (indel)polymorphism located 64 bp upstream of the first untranslanted exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays the authors show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay they show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of CGGG indel. The same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.