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Environmental Exposures and Rheumatoid Arthritis Risk

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Abstract

In addition to rapidly burgeoning data regarding novel genetic risk factors, a growing list of environmental exposures have been implicated in rheumatoid arthritis (RA) susceptibility. Cigarette smoking is chief among the many environmental exposures implicated in disease risk, accounting for approximately one in six new cases of RA, with recent results underscoring the central importance of select gene–smoking interactions in RA development. In this review, we examine data linking several environmental exposures with RA risk, including cigarette smoking, other air pollutants and occupational exposures, reproductive/hormonal influences, alcohol consumption, select infections leading to periodontal disease, and dietary factors. Where applicable, we review the current understanding of biologic mechanisms linking these environmental factors to disease risk.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Vessey MP, Villard-Mackintosh L, Yeates D. Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception. 1987;35:457–64.

    Article  PubMed  CAS  Google Scholar 

  2. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46.

    Article  PubMed  CAS  Google Scholar 

  3. Karlson E, Lee I, Cook N, Manson J, Buring J, Hennekens C. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum. 1999;42:910–7.

    Article  PubMed  CAS  Google Scholar 

  4. Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A. Smoking and risk of rheumatoid arthritis. J Rheumatol. 1993;20:1830–5.

    PubMed  CAS  Google Scholar 

  5. Symmons DP, Bankhead C, Harrison BJ, Brennan P, Barrett E, Scott DG, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum. 1997;40:1955–61.

    Article  PubMed  CAS  Google Scholar 

  6. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50:3085–92.

    Article  PubMed  CAS  Google Scholar 

  7. Criswell LA, Merlino LA, Cerhan JR, Mikuls TR, Mudano AS, Burma M, et al. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women’s Health Study. Am J Med. 2002;15:465–71.

    Article  Google Scholar 

  8. Silman A, Newman J, MacGregor A. Cigarette smoking increases the risk of rheumatoid arthrits. Arthritis Rheum. 1996;39(5):732–5.

    Article  PubMed  CAS  Google Scholar 

  9. Voigt L, Koepsell T, Nelson JL, Dugowson C, Daling J. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiology. 1994;5:525–32.

    PubMed  CAS  Google Scholar 

  10. Uhlig T, Hagen K, Kvien T. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol. 1999;26:47–54.

    PubMed  CAS  Google Scholar 

  11. • Karlson EW, Chang SC, Cui J, Chibnik LB, Fraser PA, Devivo I, et al.: Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident RA. Ann Rheum Dis. 2009. In this prospective study, investigators showed the importance of accounting for cumulative smoking exposure in examining gene–smoking interactions in RA.

  12. • Mikuls TR, Sayles H, Yu F, Levan T, Gould KA, Thiele GM, et al.: Associations of cigarette smoking with rheumatoid arthritis in African Americans. Arthritis Rheum. 2010:62;3560–8. This was the first study to show that cigarette smoking is associated with increased RA risk in African Americans.

    Article  PubMed  Google Scholar 

  13. Costenbader KH, Feskanich D, Mandl LA, Karlson EW: Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med. 2006:119(6);503 e501–509.

    Google Scholar 

  14. Mahdi H, Fisher BA, Kallberg H, Plant D, Malmstrom V, Ronnelid J, et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009;41(12):1319–24.

    Article  PubMed  CAS  Google Scholar 

  15. Snir O, Widhe M, von Spee C, Lindberg J, Padyukov L, Lundberg K, et al.: Multiple antibody reactivities to citrullinated antigens in sera from rheumatoid arthritis patients—association with HLA-DRB1 alleles. Ann Rheum Dis. 2008.

  16. • Kallberg H, Ding B, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, et al.: Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011:70(3);508–11. This recently published report quantified the combined contribution of smoking and HLA-DRB1 SE alleles in RA risk.

    Article  PubMed  Google Scholar 

  17. Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin JM. Genetic polymorphisms and lung cancer suspectibility: a review. Lung Cancer. 2002;37:241–56.

    Article  PubMed  Google Scholar 

  18. Miller MC, Mohrenweiser HW, Bell DA. Genetic variability in susceptibility and response to toxicants. Toxicol Lett. 2001;130:269–80.

    Article  Google Scholar 

  19. Bouchardy C, Benhamou S, Jourenkova N, Dayer P, Hirvonen A. Metabolic genetic polymorphisms and suspectibility to lung cancer. Lung Cancer. 2001;32:109–12.

    Article  PubMed  CAS  Google Scholar 

  20. Mattey DL, Hassell AB, Plant M, Dawes PT, Ollier WR, Jones PW, et al. Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope. Ann Rheum Dis. 1999;58:164–8.

    Article  PubMed  CAS  Google Scholar 

  21. Criswell LA, Saag KG, Mikuls TR, Cerhan JR, Merlino LA, Lum RF, et al. Smoking interacts with genetic risk factors in the development of rheumatoid arthritis among older Caucasian women. Ann Rheum Dis. 2006;65(9):1163–7.

    Article  PubMed  CAS  Google Scholar 

  22. • Keenan BT, Chibnik LB, Cui J, Ding B, Padyukov L, Kallberg H, et al.: Effect of interactions of glutathione S-transferase T1, M1, and P1 and HMOX1 gene promoter polymorphisms with heavy smoking on the risk of rheumatoid arthritis. Arthritis Rheum. 2010:62(11);3196–210. This study shows that non-HLA genes also contribute to gene–smoking interactions in RA risk; the report shows significant interactions of smoking with the GSTT1-null genotype in RA susceptibility.

    Article  PubMed  Google Scholar 

  23. Mikuls TR, Gould KA, Bynote KK, Yu F, Levan TD, Thiele GM, et al. Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study. Arthritis Res Ther. 2010;12(6):R213.

    Article  PubMed  Google Scholar 

  24. Nalbandian G, Kovats S. Estrogen, immunity & autoimmune disease. Curr Med Chem. 2005;5:85–91.

    CAS  Google Scholar 

  25. • Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, et al.: Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008:67(10);1488–92. This report provides “mechanistic” insight into the link between smoking and ACPA-positive disease, showing that smoking leads to increased PAD expression and citrullination in bronchoalveolar lavage specimens.

    Article  PubMed  CAS  Google Scholar 

  26. Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect. 2009;117(7):1065–9.

    Article  PubMed  CAS  Google Scholar 

  27. Brown JM, Pfau JC, Pershouse MA, Holian A. Silica, apoptosis, and autoimmunity. J Immunotoxicol. 2005;1(3):177–87.

    Article  PubMed  Google Scholar 

  28. Noonan CW, Pfau JC, Larson TC, Spence MR. Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect. 2006;114(8):1243–7.

    Article  PubMed  CAS  Google Scholar 

  29. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax. 1953;8:29–35.

    Article  PubMed  CAS  Google Scholar 

  30. • Stolt P, Yahya A, Bengtsson C, Kallberg H, Ronnelid J, Lundberg I, et al.: Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis. 2010:69(6);1072–6. This Swedish case-control study implicated occupational exposure to silica dust as a risk factor for RA development.

    Article  PubMed  CAS  Google Scholar 

  31. Parks CG, Conrad K, Cooper GS. Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect. 1999;107 Suppl 5:793–802.

    Article  PubMed  Google Scholar 

  32. Pikwer M, Bergstrom U, Nilsson JA, Jacobsson L, Berglund G, Turesson C. Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis. Ann Rheum Dis. 2009;68(4):526–30.

    Article  PubMed  CAS  Google Scholar 

  33. Doran MF, Crowson CS, O’Fallon WM, Gabriel SE. The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study. J Rheumatol. 2004;31(2):207–13.

    PubMed  CAS  Google Scholar 

  34. Walitt B, Pettinger M, Weinstein A, Katz J, Torner J, Wasko MC, et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women’s health initiative randomized controlled trials. Arthritis Rheum. 2008;59(3):302–10.

    Article  PubMed  Google Scholar 

  35. Brennan P, Silman A. Breast-feeding and the onset of rheumatoid arthritis. Arthritis Rheum. 1994;37(6):808–13.

    Article  PubMed  CAS  Google Scholar 

  36. Karlson EW, Mandl LA, Hankinson SE, Grodstein F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses’ Health Study. Arthritis Rheum. 2004;50(11):3458–67.

    Article  PubMed  Google Scholar 

  37. Merlino LA, Cerhan JR, Criswell LA, Mikuls TR, Saag KG. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum. 2003;33:72–82.

    Article  PubMed  CAS  Google Scholar 

  38. • Kallberg H, Jacobsen S, Bengtsson C, Pedersen M, Padyukov L, Garred P, et al.: Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case-control studies. Ann Rheum Dis. 2009:68(2);222–227. This investigation suggests that alcohol consumption may be protective against RA onset.

    Article  PubMed  CAS  Google Scholar 

  39. Maxwell JR, Gowers IR, Moore DJ, Wilson AG. Alcohol consumption is inversely associated with risk and severity of rheumatoid arthritis. Rheumatology (Oxford). 2010;49(11):2140–6.

    Article  CAS  Google Scholar 

  40. Cerhan JR, Saag KG, Criswell LA, Merlino LA, Mikuls TR. Blood transfusion, alcohol use, and anthropometric risk factors for rheumatoid arthritis in older women. J Rheumatol. 2002;29:246–54.

    PubMed  Google Scholar 

  41. Waldschmidt TJ, Cook RT, Kovacs EJ. Alcohol and inflammation and immune responses: summary of the 2005 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol. 2006;38(2):121–5.

    Article  PubMed  Google Scholar 

  42. Lu B, Solomon DH, Costenbader KH, Keenan BT, Chibnik LB, Karlson EW. Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis. Arthritis Rheum. 2010;62(12):3554–9.

    Article  PubMed  CAS  Google Scholar 

  43. Jonsson IM, Verdrengh M, Brisslert M, Lindblad S, Bokarewa M, Islander U, et al. Ethanol prevents development of destructive arthritis. Proc Natl Acad Sci USA. 2007;104(1):258–63.

    Article  PubMed  CAS  Google Scholar 

  44. • Dissick A, Redman RS, Jones M, Rangan BV, Reimold A, Griffiths GR, et al.: Association of periodontitis with rheumatoid arthritis: a pilot study. J Periodontol. 2010:81(2);223–30. This case-control study conducted in US veterans shows that PD is about two times more common in RA than osteoarthritis. In patients with RA, PD is associated with ACPA positivity.

    Article  PubMed  Google Scholar 

  45. Kasser UR, Gleissner C, Dehne F, Michel A, Willershausen-Zonnchen B, Bolten WW. Risk for periodontal disease in patients with longstanding rheumatoid arthritis. Arthritis Rheum. 1997;40:2248–51.

    Article  PubMed  CAS  Google Scholar 

  46. Mercado FB, Marshall RI, Bartold PM. Inter-relationships between rheumatoid arthritis and periodontal disease. A review. J Clin Periodontol. 2003;30:761–72.

    Article  PubMed  CAS  Google Scholar 

  47. • Wegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K, et al.: Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010:62(9);2662–72. This study confirms that P. gingivalis citrullinates human fibrinogen, supporting the hypothesis that infection with this organism could play a role in tolerance loss in RA.

    Article  PubMed  CAS  Google Scholar 

  48. Lundberg K, Kinloch A, Fisher BA, Wegner N, Wait R, Charles P, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008;58(10):3009–19.

    Article  PubMed  CAS  Google Scholar 

  49. • Mikuls TR, Payne JB, Reinhardt RA, Thiele GM, Maziarz E, Cannella AC, et al.: Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol. 2009:9(1);38–42. In this study, immunity to P. gingivalis was more common in individuals with RA than in controls. In those with RA, immunity to P. gingivalis was associated with ACPA expression but not rheumatoid factor expression.

    Article  PubMed  CAS  Google Scholar 

  50. Hitchon CA, Chandad F, Ferucci ED, Willemze A, Ioan-Facsinay A, Van der Woude D, et al. Antibodies to Porphyromonas gingivalis are associated with anti-citrullinated protein antibodies in RA patients and their relatives. J Rheumatol. 2010;37:1105–12.

    Article  PubMed  CAS  Google Scholar 

  51. Sato M, Miyazaki T, Nagaya T, Murata Y, Ida N, Maeda K, et al. Antioxidants inhibit tumor necrosis factor-alpha mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells. J Rheumatol. 1996;23(3):432–8.

    PubMed  CAS  Google Scholar 

  52. Aaseth J, Haugen M, Forre O. Rheumatoid arthritis and metal compounds—perspectives on the role of oxygen radical detoxification. Analyst. 1998;123(1):3–6.

    Article  PubMed  CAS  Google Scholar 

  53. Cerhan JR, Saag KG, Merlino LA, Mikuls TR, Criswell LA. Antioxidant micronutrients and risk of rheumatoid arthritis in a cohort of older women. Am J Epidemiol. 2003;15:345–54.

    Article  Google Scholar 

  54. Comstock GW, Burke AE, Hoffman SC, Helzlsouer KJ, Bendich A, Masi AT, et al. Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 1997;56(5):323–5.

    Article  PubMed  CAS  Google Scholar 

  55. Kerr GS, Sabahi I, Richards JS, Caplan L, Cannon GW, Reimold A, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol. 2010;38(1):53–9.

    Article  PubMed  Google Scholar 

  56. Patel S, Farragher T, Berry J, Bunn D, Silman A, Symmons D. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 2007;56(7):2143–9.

    Article  PubMed  CAS  Google Scholar 

  57. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum. 2004;50:72–7.

    Article  PubMed  CAS  Google Scholar 

  58. Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis. 2008;67(4):530–5.

    Article  PubMed  CAS  Google Scholar 

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Hoovestol, R.A., Mikuls, T.R. Environmental Exposures and Rheumatoid Arthritis Risk. Curr Rheumatol Rep 13, 431–439 (2011). https://doi.org/10.1007/s11926-011-0203-9

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