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Advances in identifying genetic and non-genetic risk factors of rheumatoid arthritis

Advances in identifying genetic and non-genetic risk factors of rheumatoid arthritis. Jessica Larson Advisor: Sam Powdrill, PA-C. Objectives. Review of epidemiology & pathophysiology of RA Understand functional impairment

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Advances in identifying genetic and non-genetic risk factors of rheumatoid arthritis

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  1. Advances in identifying genetic and non-genetic risk factors of rheumatoid arthritis Jessica Larson Advisor: Sam Powdrill, PA-C

  2. Objectives • Review of epidemiology & pathophysiology of RA • Understand functional impairment • Learn risk factors that determine the onset & severity in development of RA • Pre-RA red flags • How to advise patient in clinic to reduce or prolong outcome of RA

  3. Epidemiology • Most common inflammatory polyarthritis • One percent or 2.1 million adults in US • Women 2-3x more affected than men • Age of onset is 40-60 years old • Smokers 4x more likely to develop • First-degree relative prevalence rate is 2-3x more like to develop • Mortality is higher, in severe RA mortality approaches that of CHF or Hodgkin disease

  4. Pathophysiology Review http://www.hopkins-arthritis.org/rheumatoid/rheum_clin_path.html#preven

  5. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  6. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Morning stiffness >1 hour http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  7. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Arthritis of >3 of the following joints: PIP, MCP, wrist, elbow, knee, ankle, and MTP joints http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  8. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Symmetric involvement of joints http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  9. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Rheumatoid nodules http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  10. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Positive serum rheumatoid factor http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  11. Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg Radiographic changes including erosions or bony decalcification http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg

  12. Risk Factors

  13. GENETIC HLA - DR complex DR-1 & DR-4 NIMA & NIPA HLA - I kappa BL NON-GENETIC Smoking Neuroendocrine imbalances: Low sex hormones Low cortisol levels Vascular endothelial alterations in men Immunologic markers Risk Factors

  14. Pre-RA red flags CCP antibody immunological markers appear many years (as many as 12) before onset of RA with increased risks if: • Smoking (>20 pack-years) • Coffee consumption (>10 cups/day) • Ever use of oral contraceptives • First-degree relative of schizophrenia • Obesity (3x risk) • Age of menarche >15 years old (2x risk)

  15. What can PAs do? • If there is a family history of RA, it is especially important to NOT SMOKE • Anti-CCP test is a blood test that can be ordered by the PA • RF is ~81-87% specific post-onset • CCP is ~96% specific and available earlier • Tell them to stay active and loose weight

  16. References • Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-324. • Barrera P, et al. Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF). Rheumatol. 2001 May;28(5):968-74. PMID: 1136122 • Berg L, Ronnelid J, Sanjeevi CB, Lampa J, Klareskog L. Interferon-gamma production in response to in vitro stimulation with collagen type II in rheumatoid arthritis is associated with HLA-DRB1(*)0401 and HLA-DQ8. Arthritis Res. 2000;2(1):75-84. PMID: 11219392 • Combe B, Eliaou JF. Can the prognosis of early rheumatoid arthritis be predicted? Presse Med. 1995 May 20;24(18):839-41. PMID: 7638113 • Cornelis F, Faure S, Martinez M, Prud’homme JF, Fritz P, Dib C, et al. New susceptibility locus for rheumatoid arthritis suggested by RA susceptibility genes in multicase families 915 a genome-wide linkage study. Proc Natl Acad Sci U S A 1998;95: 10746–50. • 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 Jun;119(6):503.e1-9. )PMID: 16750964 • Cutolo M, Villaggio B, Foppiani L, Briata M, Sulli A, Pizzorni C, Faelli F, Prete C, Felli L, Seriolo B, Giusti M. The hypothalamic-pituitary-adrenal and gonadal axes in rheumatoid arthritis. Ann N Y Acad Sci. 2000;917:835-43. Review. PMID: 11268413 • Evans TI, Han J, Singh R, Moxley G. The genotypic distribution of shared-epitope DRB1 alleles suggests a recessive mode of inheritance of the rheumatoid arthritis disease-susceptibility gene. Arthritis Rheum. 1995 Dec;38(12):1754-61. PMID: 884934 • Goronzy JJ, Weyand CM. Interplay of T lymphocytes and HLA-DR molecules in rheumatoid arthritis. Curr Opin Rheumatol. 1993 Mar;5(2):169-77. Review. PMID: 8452767 • Geenen R, Van Middendorp H, Bijlsma JW. Related Articles, The impact of stressors on health status and hypothalamic-pituitary-adrenal axis and autonomic nervous system responsiveness in rheumatoid arthritis. Ann N Y Acad Sci. 2006 Jun;1069:77-97. PMID: 16855136 • Harney S, Newton J, Milicic A, Brown MA, Wordsworth BP. Non-inherited maternal HLA alleles are associated with rheumatoid arthritis. Rheumatology (Oxford). 2003 Jan;42(1):171-4. PMID: 12509632) • Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990;322:1277–89. • Hutchinsona D, Shepstoneb L, et al., Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA, Ann Rheum Dis 2001;60:223-227 • van der Horst-Bruinsma IE, Hazes JM, Schreuder GM, Radstake TR, Barrera P, van de Putte LB, Mustamu D, van Schaardenburg D, Breedveld FC, de Vries RR. Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis. Ann Rheum Dis. 1998 Nov;57(11):672-5. PMID: 9924209 • van Jaarsveld CH, Otten HG, Jacobs JW, Kruize AA, Brus HL, Bijlsma JW. Is there an indication for HLA-DR typing for individual patients with rheumatoid arthritis? Clin Exp Rheumatol. 1998 Jul-Aug;16(4):483-8. Review. PMID: 9706434 • Jawaheer D, Seldin MF, Amos CI, et. Al. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum. 2003 Apr;48(4):906-16. • Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Monteiro J, et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001;68:927–36. • Kilding R, Wilson AG. Mapping of a novel susceptibility gene for rheumatoid arthritis in the telomeric MHC region. Cytokine. 2005 Oct 21;32(2):71-5. Epub 2005 Sep 30. Review. PMID: 1619916 • Klareskog L, Padyukov L, Lorentzen J, Alfredsson L. Related Articles, Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Aug;2(8):425-33. Review.PMID: 16932734) • Matsumoto A. Rheumatoid arthritis, a clinical presentation. Johns Hopkins University website. http://www.hopkins-arthritis.com/rheumatoid/rheum_clin_pres.html • MacKay K, Eyre S, Myerscough A, Milicic A, Barton A, Laval S, et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum 2002;46:632–9 • Masi AT, Bijlsma JW, Chikanza IC, Pitzalis C, Cutolo M. Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: physiopathogenetic and therapeutic perspectives. Semin Arthritis Rheum. 1999 Oct;29(2):65-81. Review. PMID: 10553979) • Masi AT, Aldag JC, Jacobs JW. Rheumatoid arthritis: neuroendocrine immune integrated physiopathogenetic perspectives and therapy. Rheum Dis Clin North Am. 2005 Feb;31(1):131-60, x. Review. PMID: 15639060) • Masi AT, Aldag JC. Integrated neuroendocrine immune risk factors in relation to rheumatoid arthritis: should rheumatologists now adopt a model of a multiyear, presymptomatic phase? Scand J Rheumatol. 2005 Sep-Oct;34(5):342-52. Review. PMID: 16234181) • Masi AT, Aldag JC, Chatterton RT. Sex hormones and risks of rheumatoid arthritis and developmental or environmental influences. Ann N Y Acad Sci. 2006 Jun;1069:223-35. Review. PMID: 16855149)

  17. References (cont) • Mattey DL, Dawes PT, Gonzalez-Gay MA, Garcia-Porrua C, Thomson W, Hajeer AH, Ollier WE. HLA-DRB1 alleles encoding an aspartic acid at position 70 protect against development of rheumatoid arthritis.J Rheumatol. 2001 Feb;28(2):232-9. PMID: 11246655 • Okamoto K, Makino S, Yoshikawa Y, Takaki A, Nagatsuka Y, Ota M, Tamiya G, Kimura A, Bahram S, Inoko H. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet. 2003 Feb;72(2):303-12. Epub 2002 Dec 31. • Ollier W, Thomson W. Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am 1992;18:741–59. • Pedersen M, Jacobsen S, Klarlund M, Pedersen BV, Wiik A, Wohlfahrt J, Frisch M. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res Ther. 2006;8(4):R133. PMID: 1687251 • Scand J Rheumatol, HLA antigens in rheumatoid arthritis patients with and without a family history of polyarthritis.. 1985;14(4):375-80. PMID: 4081661 • Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978;298:869–71. • Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L; EIRA study group. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003 Sep;62(9):835-41. Review. PMID: 12922955) • de Vries RR, Huizinga TW, Toes RE. Redefining the HLA and RA association: to be or not to be anti-CCP positive. J Autoimmun. 2005;25 Suppl:21-5. Epub 2005 Oct 27. Review. PMID: 16257178 • Weyand CM, Klimiuk PA, Goronzy JJ. Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol. 1998;20(1-2):5-22. • en.wikipedia.org/wiki/Human_leukocyte_antigen

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