478285 2013

JRA0010.1177/1470320313478285Journal of the Renin-Angiotensin-Aldosterone SystemSong et al.

Original Article

The angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to rheumatoid arthritis, vitiligo and psoriasis: A meta-analysis

Journal of the Renin-AngiotensinAldosterone System 2015, Vol. 16(1) 195­–202 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320313478285 jra.sagepub.com

Gwan Gyu Song1, Sang-Cheol Bae2, Jae-Hoon Kim1 and Young Ho Lee1

Abstract Introduction: The purpose of this study was to examine whether the insertion (I) and deletion (D) of angiotensinconverting enzyme (ACE) polymorphism confers susceptibility to psoriasis, vitiligo and rheumatoid arthritis (RA). Materials and methods: A meta-analysis was conducted on the association between the ACE I/D polymorphisms and psoriasis, vitiligo and RA. Results: Fifteen studies comprising five on psoriasis, five on vitiligo and five on RA were available for the meta-analysis consisting of 2094 cases and 2871 controls. Meta-analysis of the DD+ID genotype showed significant associations with psoriasis (odds ratio (OR) 0.753, 95% confidence interval (CI) 0.601–0.921, p = 0.006). Meta-analysis showed no association between vitiligo and the ACE I/D polymorphism. Meta-analysis of the DD+ID genotype showed an association with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001). Ethnicity-specific meta-analysis of the D allele showed no association with psoriasis in Europeans, and vitiligo in South Asians. However, subgroup analysis by ethnicity revealed a significant association between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10−5). Conclusions: Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to RA, especially in Arab populations. Keywords Angiotensin-converting enzyme, meta-analysis, polymorphism, psoriasis, vitiligo, rheumatoid arthritis Date received: 29 October 2012; accepted: 09 August 2014

Introduction Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and increased blood flow induced by the stimulation of tissue-resident immune cells by markedly altered cutaneous cytokine profiles.1,2 Vitiligo is a progressive depigmenting disorder characterized by the loss of functional melanocytes from the epidermis and affects 1–2% of the world population.3 Rheumatoid arthritis (RA) is a chronic inflammatory disease of predominantly synovial joints that causes significant morbidity and shortens life expectancy.4 Although the etiology of these diseases is not fully understood, interactions between a susceptible genetic background and environmental factors have been suggested.5 Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II and inactivates bradykinin via the kallikrein–kininogen system.6 Angiotensin II is the main effector molecule of the renin–angiotensin–system (RAS), is pleiotropic, and is a mediator of the development and progression of diseases.7 Furthermore, angiotensin II is

a potent pro-inflammatory modulator that augments and perpetuates the immune response.7 The ACE gene, located on chromosome 17q23, contains an insertion (I)/deletion (D) polymorphism within intron 16 that may contain or lack a 287 bp repeat sequence.8 The DD genotype is associated with approximately a two-fold higher tissue and plasma concentration of ACE than the II genotype.8 Thus, it seems possible that the D allele could play a role in the pathogenesis of autoimmune diseases.

1Division

of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea 2Division of Rheumatology, Department of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, Korea Corresponding author: Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. Email: [email protected]

196 The ACE I/D polymorphism has been studied in the context of autoimmune disease. However, published results on the genetic association for the ACE I/D polymorphism are controversial and inconclusive.9–22 This may be due to small sample sizes, low statistical power, and/or clinical heterogeneity. In order to overcome the limitations of individual studies, resolve inconsistencies and reduce the likelihood that random errors are responsible for false-positive or false-negative associations, we employed meta-analysis to further characterize the association. In the present study,23–25 we used meta-analysis to investigate whether the ACE I/D polymorphism contributes to susceptibility to psoriasis, vitiligo and RA.

Materials and methods Identification of eligible studies and data extraction A literature search was conducted for studies that examined the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA. We utilized the MEDLINE and EMBASE citation indices to identify articles in which the ACE I/D polymorphism was determined in patients and controls (up to October 2012). In addition, all references mentioned in the identified articles were reviewed to identify studies not indexed by MEDLINE and EMBASE. The following keywords and subject terms were searched: ‘angiotensin-converting enzyme’, ‘ACE’, ‘psoriasis’, ‘vitiligo’, ‘rheumatoid arthritis’, and ‘RA’. Studies were included in the analysis if they: (1) were case control studies; (2) contained original data; and (3) contained sufficient data to calculate odds ratios (ORs). No language restriction was applied. We excluded the following: (1) studies containing overlapping data; (2) studies in which the number of null and wild genotypes or alleles could not be ascertained; and (3) studies in which family members had been studied because their analysis was based on linkage considerations. The following information was extracted from each identified study: author, year of publication, ethnicity of the study population, demographics, numbers of cases and controls and the frequencies of the genotypes and alleles of the ACE I/D polymorphism.

Evaluation of publication bias and study quality Funnel plots are used to detect publication bias, but they require a range of studies of varying sizes and subjective judgments, and thus, we evaluated publication bias using Egger’s linear regression test.26 The Egger’s linear regression test measures funnel plot asymmetry on a natural logarithmic scale of ORs. The chi-square test was used to determine whether observed genotype frequencies in controls conformed to Hardy–Weinberg (H-W) expectations.

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Evaluation of statistical associations We performed meta-analyses using: (1) the allelic contrast (D vs. I); (2) the recessive (DD vs. ID + II); (3) the dominant (DD + ID vs. II); and (4) the homozygote contrast (DD vs. II) models. Point estimates of risks, ORs and 95% confidence intervals (CIs) were estimated for each study. In addition, within- and between-study variations and heterogeneities were assessed using Cochran’s Q-statistic. Cochran’s Q-statistic test assesses the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity was quantified using I2, with a range between 0 and 100%, and represents the proportion of between-study variability attributable to heterogeneity rather than chance.27 I2 values of 25%, 50% and 75% were nominally assigned as low, moderate and high estimates. The fixed effects model assumes that a genetic factor has a similar effect on disease susceptibility across all studies investigated and that observed variations among studies are caused by chance alone.28 The random effects model assumes that different studies show substantial diversity and assesses both withinstudy sampling error and between-study variance.29 When study groups are homogeneous, the two models are similar. If the study groups lack homogeneity, the random effects model usually provides wider CIs than the fixed effects model. The random effects model is most appropriate in the presence of significant between-study heterogeneity.29 Statistical manipulations were undertaken using a Comprehensive Meta-Analysis computer program (Biosta, Englewood, NJ, USA). The power of each study was computed as the probability of detecting an association between the ACE polymorphism and vasculitis using a significance level of 0.05 and assuming an OR of 1.5 (small effect size). Power analysis was performed using the statistical program G*Power (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower).

Results Studies included in the meta-analysis Twenty studies were identified by electronic and manual searches and 15 were selected for a full-text review based on title and abstract details.9–22,30 One study was excluded because it contained duplicate data.30 One eligible study contained data on two different RA groups, and these were treated independently.21 Thus, a total of 15 separate comparisons met our inclusion criteria.9–22 These studies comprised five each on psoriasis, vitiligo and RA. They consisted of four European, three East Asian, three Arab, three Turkish and two South Asian studies. In total the studies included 2094 cases and 2871 controls. Selected details of the individual studies are summarized in Table 1. The statistical power of these 15 studies ranged from 16.4% to 86.1%. One of the studies had a statistical power exceeding 80%.12

European European Arab East Asian Turkish South Asian Turkish South Asian European East Asian Turkish Arab Arab European East Asian

Spain Austria Kuwait Taiwan Turkey India Turkey India UK Korea Turkey Kuwait Egypt UK UK

Coto-Segura et al., 20099 Weger et al., 200710 Al-Awadhi et al., 200711 Chang et al., 200712 Ozkur et al., 200413 Tippisetty et al., 201114 Pehlivan et al., 200915 Dwivedi et al., 200816 Akhtar et al., 200517 Jin et al., 200418 Yigit et al., 201219 Uppal et al., 200720 Ahmed et al., 201222 Ghelani et al.-1, 201121 Ghelani et al.-2, 201221 Total

Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis Vitiligo Vitiligo Vitiligo Vitiligo Vitiligo RA RA RA RA RA

Disease

 268   207   51  312   86  272   48  125  106  120  110   60   66  135  128 2094

 272  182  100  615  154  205   50  156  174  429  146   35   66  140  147 2871

62.7 48.3 67.6 27.6 62.8 48.3 55.2 38.8 49.5 48.3 51.4 74.2 76.5 55.9 42.2 49.7

60.8 55.2 63.5 31.8 59.4 40.0 57.0 43.6 53.4 39.3 36.0 52.9 53.8 55.4 42.9 45.4

Control

Case

Case

Control

D allele (%)

Numbers

RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; H-W: Hardy–Weinberg. aPower calculations assume α = 0.05, OR = 1.5.

Ethnicity

Country

Author

Table 1.  Details of the individual studies included in the meta-analysis.

1.081 0.758 1.202 0.817 0.820 0.855 0.930 2.561 2.799 1.023 0.973 1.081 0.758 1.202 1.153 1.160

OR 0.846 0.571 0.725 0.660 0.585 0.607 0.529 1.374 1.651 0.731 0.693 0.846 0.571 0.725 0.785 0.975

95% CI

Association

1.382 1.005 1.991 1.010 1.151 1.203 1.635 4.771 4.747 1.433 1.366 1.382 1.005 1.991 1.692 1.381

0.534 0.054 0.475 0.062 0.252 0.368 0.801 0.003 0.000 0.893 0.874 0.534 0.054 0.475 0.468 0.094

p-value

0.050 0.653 0.770 0.873 0.378 0.007 0.663 0.658 0.829 0.145 0.1).

Discussion ACE is expressed in a wide range of tissues including those of the kidneys, heart, lungs, vascular endothelium, skin,

joints and testes. ACE plays an important role in RAS, and angiotensin II conversion, directly increases vascular smooth muscle cell contraction and affects smooth muscle proliferation, monocyte adhesion, platelet adhesion, and aggregation. Angiotensin II also acts as a potent proinflammatory modulator.7,31 The ACE I/D polymorphism is located on an intron of the ACE gene, and is in strong linkage disequilibrium with genetic factors that influence serum ACE levels.8 In fact, the ACE I/D polymorphism accounts for approximately one-half of the variance in ACE plasma levels in humans. Furthermore, the polymorphism has been studied in several diseases, including Alzheimer’s

200

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Table 3.  Meta-analysis of the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA in each ethnic group. Diseases (comparison) Population

Psoriasis (D vs. I)       Vitiligo (D vs. I)       RA (D vs. I)      

European East Asian Turkish Arab European South Asian East Asian Turkish European East Asian Turkish Arab

No. of studies

2 1 1 1 1 2 1 1 1 1 1 2

Test of association

Test of heterogeneity

OR

95% CI

p-value

Model

p-value

I2

0.912 0.817 1.153 1.202 0.855 1.086 1.446 0.930 1.023 0.973 1.881 2.697

0.644–1.291 0.660–1.010 0.785–1.692 0.725–1.991 0.607–1.203 0.642–1.837 1.084–1.929 0.529–1.635 0.731–1.473 0.693–1.366 1.317–2.686 1.803–4.034

0.602 0.062 0.468 0.475 0.368 0.759 0.012 0.801 0.893 0.874 0.001 1.3 × 10−5

R NA NA NA NA R NA NA NA NA NA F

0.063 NA NA NA NA 0.014 NA NA NA NA NA 0.831

75.0 NA NA NA NA 83.5 NA NA NA NA NA 0

ACE I/D: angiotensin-converting enzyme insertion and deletion; RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; F: fixed effects model; D: deletion; I: insertion; R: random effects model.

disease, myocardial infarction, cerebral infarction, hypertension and diabetic nephropathy. These studies also reported associations between susceptibilities to these diseases and the DD genotype and D allele.9–22 In this meta-analysis, we combined evidence on the associations between the ACE I/D polymorphism and susceptibility to psoriasis, vitiligo and RA. Meta-analysis of the DD+ID genotype showed significant associations with psoriasis (OR 0.753, 95% CI 0.601–0.921, p = 0.006), whereas no such relation was found for vitiligo. In addition, meta-analysis of the DD+ID genotype showed an association with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001). Subgroup analysis by ethnicity revealed a significant association between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10−5). ACE is expressed by skin components such as vascular endothelial cells, fibroblasts, and keratinocytes.32,33 It has been known that administration of ACE inhibitors can induce or exacerbate psoriasis in clinical practice.34 Tissue ACE can control the cutaneous inflammatory response by degrading bradykinin and substance P, which are strong mediators of inflammation.35 Activation of the kallikrein–kininogen system in plasma and tissue has been associated with psoriasis.36 Moreover, in view of the fact that the ACE I/D polymorphism accounts for approximately one-half of the variance in ACE plasma levels, it is likely that the ACE I/D polymorphism plays a role in susceptibility to psoriasis.8 This finding suggests that the ACE II genotype reduces ACE activity in skin and may augment the activation of the kallikrein– kininogen system and increase the risk of psoriasis.12 Although the etiology of vitiligo has not been determined, autoimmune destruction of melanocytes has been suggested. Genetic studies have established that vitiligo susceptibility has a genetic component.37,38 In the present

study, we found no association between vitiligo and the ACE I/D polymorphism. The lack of association between vitiligo and psoriasis is unclear. The difference may be due to small sample sizes or differences in the type of skin disease. These two disorders may follow different pathways at the cellular and molecular levels. Relatively few studies reported the association between vitiligo and the ACE I/D polymorphism and their results were heterogeneous. Further studies are required on this topic. ACE, as a key regulator in inflammatory signal transduction pathway, has been considered to be involved in the pathogenesis of RA.39 ACE levels are increased in RA synovial fluid suggesting that locally produced ACE may contribute to the joint destruction of RA.40 ACE converts angiotensin I to angiotensin II, which has a role as a growth factor and as a proinflammatory modulator. Angiotensin II modulates the expression of many cytokines, chemokines, adhesion molecules, endothelin-1, prostaglandins, plateletactivating factor, nitric oxide and cyclooxygenase-2.39 Our results should be interpreted with caution due to the limited number of studies included in this meta-analysis, which restricted further sub-group analyses. The relative importance of the ACE I/D polymorphism during the development of autoimmune diseases may be dependent on ethnicity. However, we were unable to perform ethnicityspecific meta-analysis due to limited data. Thus, further studies are required to allow meta-analysis by ethnic group to clarify the role of the ACE I/D polymorphism in various ethnic populations. Our study has several limitations including potential publication bias, heterogeneity and confounding factors that may have distorted the meta-analysis. Secondly, there are varying levels of severity for each disease and the activity level in each disease was unclear. Further research is

Song et al. required to examine whether an association exists between the ACE I/D polymorphism and the activity or clinical features of the diseases. This was not possible in the present study due to limited data. In conclusion, this meta-analysis of the ACE I/D polymorphism based on a total sample of 2094 patients and 2871 controls demonstrates that the ACE I/D polymorphism is associated with susceptibility to RA, especially in Arab populations. Accordingly, our findings support the notion that the ACE I/D polymorphism plays a role in the pathogenesis of RA. Larger scale studies in populations with different ethnicities are required to explore relationships between polymorphisms of the ACE gene and the pathogenesis of psoriasis and RA. Conflict of interest None declared. Funding This work was supported by the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (grant no. A102065). References 1. Bhalerao J and Bowcock AM. The genetics of psoriasis: A complex disorder of the skin and immune system. Hum Mol Genet 1998; 7: 1537–1545. 2. Lee KH, Son MK, Ha YJ, et al. Inflammatory polyarthritis in a patient with psoriasis: Is it psoriatic arthritis or rheumatoid arthritis? Korean J Intern Med 2010; 25: 224–226. 3. Mollet I, Ongenae K and Naeyaert JM. Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders. Dermatol Clin 2007; 25: 363–371, ix. 4. McInnes IB and Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205–2219. 5. Choi SJ, Rho YH, Ji JD, et al. Genome scan meta-analysis of rheumatoid arthritis. Rheumatology 2006; 45: 166–170. 6. Henrion D, Benessiano J and Levy BI. In vitro modulation of a resistance artery diameter by the tissue renin–angiotensin system of a large donor artery. Circ Res 1997; 80: 189–195. 7. Kranzhofer R, Schmidt J, Pfeiffer CA, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 1623–1629. 8. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–1346. 9. Coto-Segura P, Alvarez V, Soto-Sanchez J, et al. Lack of association between angiotensin I-converting enzyme insertion/deletion polymorphism and psoriasis or psoriatic arthritis in Spain. Int J Dermatol 2009; 48: 1320–1323. 10. Weger W, Hofer A, Wolf P, et al. The angiotensin-converting enzyme insertion/deletion and the endothelin -134 3A/4A gene polymorphisms in patients with chronic plaque psoriasis. Exper Dermatol 2007; 16: 993–998.

201 11. Al-Awadhi AM, Hasan EA, Sharma PN, et al. Angiotensinconverting enzyme gene polymorphism in patients with psoriatic arthritis. Rheumatol Int 2007; 27: 1119–1123. 12. Chang YC, Wu WM, Chen CH, et al. Association between the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and risk for psoriasis in a Chinese population in Taiwan. Br J Dermatol 2007; 156: 642–645. 13. Ozkur M, Erbagci Z, Nacak M, et al. Association of insertion/ deletion polymorphism of the angiotensin-converting enzyme gene with psoriasis. Br J Dermatol 2004; 151: 792–795. 14. Tippisetty S, Ishaq M, Komaravalli PL, et al. Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: Protective and predisposing effects of genotypes in disease susceptibility and progression. Eur J Dermatol 2011; 21: 173–177. 15. Pehlivan S, Ozkinay F, Alper S, et al. Association between IL4 (-590), ACE (I)/(D), CCR5 (Delta32), CTLA4 (+49) and IL1-RN (VNTR in intron 2) gene polymorphisms and vitiligo. Eur J Dermatol 2009; 19: 126–128. 16. Dwivedi M, Laddha NC, Shajil EM, et al. The ACE gene I/ D polymorphism is not associated with generalized vitiligo susceptibility in Gujarat population. Pigment Cell Melanoma Res 2008; 21: 407–408. 17. Akhtar S, Gavalas NG, Gawkrodger DJ, et al. An insertion/ deletion polymorphism in the gene encoding angiotensin converting enzyme is not associated with generalised vitiligo in an English population. Arch Dermatol Res 2005; 297: 94–98. 18. Jin SY, Park HH, Li GZ, et al. Association of angiotensin converting enzyme gene I/D polymorphism of vitiligo in Korean population. Pigment Cell Res 2004; 17: 84–86. 19. Yigit S, Inanir A, Tural S, et al. Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and rheumatoid arthritis. Gene 2012; 511: 106–108. 20. Uppal SS, Haider MZ, Hayat SJ, et al. Significant association of insertion/deletion polymorphism of the angiotensinconverting enzyme gene with rheumatoid arthritis. J Rheumatol 2007; 34: 2395–2399. 21. Ghelani AM, Samanta A, Jones AC, et al. Association analysis of TNFR2, VDR, A2M, GSTT1, GSTM1, and ACE genes with rheumatoid arthritis in South Asians and Caucasians of East Midlands in the United Kingdom. Rheumatol Int 2011; 31: 1355–1361. 22. Alsaeid K, Haider MZ and Ayoub EM. Angiotensin converting enzyme gene insertion-deletion polymorphism is associated with juvenile rheumatoid arthritis. J Rheumatol 2003; 30: 2705–2709. 23. Nath SK, Harley JB and Lee YH. Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: A meta-analysis. Hum Genet 2005; 118: 225–234. 24. Lee YH, Harley JB and Nath SK. Meta-analysis of TNF-alpha promoter -308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet 2006; 14: 364–371. 25. Lee YH, Witte T, Momot T, et al. The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: Two case-control studies and a meta-analysis. Arthritis Rheum 2005; 52: 3966–3974. 26. Egger M, Davey Smith G, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

202 27. Higgins JP and Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. 28. Egger M, Smith GD and Phillips AN. Meta-analysis: Principles and procedures. BMJ 1997; 315: 1533–1537. 29. DerSimonian R and Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188. 30. Shehab DK, Al-Jarallah KF, Al-Awadhi AM, et al. Association of angiotensin-converting enzyme (ACE) gene insertiondeletion polymorphism with spondylarthropathies. J Biomed Sci 2008; 15: 61–67. 31. Kwon CI, Park PW, Kang H, et al. The usefulness of angiotensin converting enzyme in the differential diagnosis of Crohn’s disease and intestinal tuberculosis. Korean J Intern Med 2007; 22: 1–7. 32. Noveral JP, Mueller SN and Levine EM. Release of angiotensin I-converting enzyme by endothelial cells in vitro. J Cell Physiol 1987; 131: 1–5. 33. Smallridge RC, Gamblin GT and Eil C. Angiotensin-converting enzyme: Characteristics in human skin fibroblasts. Metabolism 1986; 35: 899–904.

Journal of the Renin-Angiotensin-Aldosterone System 16(1) 34. Wolf R, Tamir A and Brenner S. Psoriasis related to angiotensin-converting enzyme inhibitors. Dermatologica 1990; 181: 51–53. 35. Scholzen TE, Stander S, Riemann H, et al. Modulation of cutaneous inflammation by angiotensin-converting enzyme. J Immunol 2003; 170: 3866–3873. 36. Poblete MT, Reynolds NJ, Figueroa CD, et al. Tissue kallikrein and kininogen in human sweat glands and psoriatic skin. Br J Dermatol 1991; 124: 236–241. 37. Le Poole IC and Luiten RM. Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmun 2008; 10: 227–243. 38. Spritz RA. The genetics of generalized vitiligo. Curr Dir Autoimmun 2008; 10: 244–257. 39. Suzuki Y, Ruiz-Ortega M and Egido J. Angiotensin II: A double-edged sword in inflammation. J Nephrol 2000; 13(Suppl. 3): S101–S110. 40. Cobankara V, Ozturk MA, Kiraz S, et al. Renin and angiotensin-converting enzyme (ACE) as active components of the local synovial renin–angiotensin system in rheumatoid arthritis. Rheumatol Int 2005; 25: 285–291.