Advances in identifying genetic and non-genetic risk factors ...

Advances in identifying genetic and non-genetic risk factors ...

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

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 Pathophysiology Review http://www.hopkins-arthritis.org/rheumatoid/rheum_clin_path.html#preven Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.jpg www.csmc.edu/images/354031_Adv_Rheumatoid_Arthritis-2sm.jpg.jpg 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 Functional Impairment www.faqs.org/health/images/uchr_06_img0591.jpg http://podiatry.curtin.edu.au/encyclopedia/rheumatoid_arthritis/figure1.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 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

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 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 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

Risk Factors GeneticHLA 40% Nongenetic 40% GeneticOther 20% Genetic-Other Genetic-HLA Non-genetic

Risk Factors GENETIC NON-GENETIC HLA - DR complex Smoking Neuroendocrine imbalances: DR-1 & DR-4 NIMA & NIPA HLA - I kappa BL

Low sex hormones Low cortisol levels Vascular endothelial alterations in men Immunologic markers 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) 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 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 HLADRB1(*)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, Prudhomme JF, Fritz P, Dib C, et al. New susceptibility locus for rheumatoid arthritis suggested by RA susceptibility genes in multicase families 915 a genomewide linkage study. Proc Natl Acad Sci U S A 1998;95: 1074650. 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;322:127789. 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 JulAug;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;68:92736. 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;46:6329 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) 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;18:74159. 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;298:86971. 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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