Seminars in Arthritis and Rheumatism
Volume 39, Issue 2 , Pages 132-143 , October 2009

Systemic Nonarticular Manifestations of Rheumatoid Arthritis: Focus on Inflammatory Mechanisms

  • Larry W. Moreland, MD

      Affiliations

    • Margaret Jane Miller Endowed Professor for Arthritis Research, University of Pittsburgh, Pittsburgh, PA
    • Corresponding Author InformationAddress reprint requests to: Larry Moreland, MD, University of Pittsburgh, S711 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, PA 15261
    • ,
  • Jeffrey R. Curtis, MD, MPH

      Affiliations

    • Assistant Professor of Medicine, University of Alabama at Birmingham, Birmingham, AL

References 

  1. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29:62–67
  2. Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med. 2004;116(Suppl 7A):50S–57S
  3. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62:722–727
  4. Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996;85:307–310
  5. Anaya JM, Diethelm L, Ortiz LA, Gutierrez M, Citera G, Welsh RA, et al. Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum. 1995;24:242–254
  6. Cohen MG, Li EK, Ng PY, Chan KL. Extra-articular manifestations are uncommon in southern Chinese with rheumatoid arthritis. Br J Rheumatol. 1993;32:209–211
  7. Cohen SB, Moreland LW, Cush JJ, Greenwald MW, Block S, Shergy WJ, et al. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis. 2004;63:1062–1068
  8. Goldring SR, Gravallese EM. Adverse effects of rheumatoid arthritis on bone remodeling. Arthritis Res Ther. 2004;6:38
  9. Jongen-Lavrencic M, Peeters HR, Wognum A, Vreugdenhil G, Breedveld FC, Swaak AJ. Elevated levels of inflammatory cytokines in bone marrow of patients with rheumatoid arthritis and anemia of chronic disease. J Rheumatol. 1997;24:1504–1509
  10. Pollard LC, Choy EH, Gonzalez J, Khoshaba B, Scott DL. Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatology (Oxford). 2006;45:885–889
  11. Riemsma RP, Rasker JJ, Taal E, Griep EN, Wouters JM, Wiegman O. Fatigue in rheumatoid arthritis: the role of self-efficacy and problematic social support. Br J Rheumatol. 1998;37:1042–1046
  12. Turesson C, Jacobsson L, Bergstrom U. Extra-articular rheumatoid arthritis: prevalence and mortality. Rheumatology (Oxford). 1999;38:668–674
  13. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol. 2004;31:2115–2120
  14. Wolfe F, Michaud K. Anemia and renal function in patients with rheumatoid arthritis. J Rheumatol. 2006;33:1516–1522
  15. Gabriel SE, Crowson CS, Kremers HM, Doran MF, Turesson C, O'Fallon WM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48:54–58
  16. Voulgari PV, Kolios G, Papadopoulos GK, Katsaraki A, Seferiadis K, Drosos AA. Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol. 1999;92:153–160
  17. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis. 2000;148:209–214
  18. Davis MC, Zautra AJ, Younger J, Motivala SJ, Attrep J, Irwin MR. Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue. Brain Behav Immun. 2008;22:24–32
  19. Glossop JR, Dawes PT, Hassell AB, Mattey DL. Anemia in rheumatoid arthritis: association with polymorphism in the tumor necrosis factor receptor I and II genes. J Rheumatol. 2005;32:1673–1678
  20. Maury CP, Liljestrom M, Laiho K, Tiitinen S, Kaarela K, Hurme M. Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis. Arthritis Rheum. 2003;48:3068–3076
  21. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood. 2002;100:474–482
  22. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776–3781
  23. Pietrangelo A, Trautwein C. Mechanisms of disease: the role of hepcidin in iron homeostasis—implications for hemochromatosis and other disorders. Nat Clin Pract Gastroenterol Hepatol. 2004;1:39–45
  24. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276
  25. Kaltwasser JP, Kessler U, Gottschalk R, Stucki G, Moller B. Effect of recombinant human erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis. J Rheumatol. 2001;28:2430–2436
  26. Mercuriali F. Epoetin alfa for autologous blood donation in patients with rheumatoid arthritis and concomitant anemia. Semin Hematol. 1996;33:18–20discussion 21
  27. Han C, Rahman MU, Doyle MK, Bathon JM, Smolen J, Kavanaugh A, et al. Association of anemia and physical disability among patients with rheumatoid arthritis. J Rheumatol. 2007;34:2177–2182
  28. Franck H, Rau R, Herborn G. Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate. Clin Rheumatol. 1996;15:163–167
  29. Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. QJM. 2001;94:309–319
  30. Hamaguchi M, Kawahito Y, Ishino H, Yoshida M, Yoshikawa T. A case report of tumor necrosis factor-alpha antibody-induced thrombocytopenia associated with emerging IgM anticardiolipin antibody in patients with scleroderma overlap/rheumatoid arthritis. Clin Rheumatol. 2007;26:988–990
  31. Pathare SK, Heycock C, Hamilton J. TNFalpha blocker-induced thrombocytopenia. Rheumatology (Oxford). 2006;45:1313–1314
  32. Kirwan JR, Minnock P, Adebajo A, Bresnihan B, Choy E, de Wit M, et al. Patient perspective: fatigue as a recommended patient centered outcome measure in rheumatoid arthritis. J Rheumatol. 2007;34:1174–1177
  33. Hewlett S, Hehir M, Kirwan JR. Measuring fatigue in rheumatoid arthritis: a systematic review of scales in use. Arthritis Rheum. 2007;57:429–439
  34. Mancuso CA, Rincon M, Sayles W, Paget SA. Psychosocial variables and fatigue: a longitudinal study comparing individuals with rheumatoid arthritis and healthy controls. J Rheumatol. 2006;33:1496–1502
  35. Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in european patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006;54:2817–2829
  36. Moreland LW, Genovese MC, Sato R, Singh A. Effect of etanercept on fatigue in patients with recent or established rheumatoid arthritis. Arthritis Rheum. 2006;55:287–293
  37. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45
  38. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton IL, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004;19:893–899
  39. Fonseca JE, Cortez-Dias N, Francisco A, Sobral M, Canhao H, Resende C, et al. Inflammatory cell infiltrate and RANKL/OPG expression in rheumatoid synovium: comparison with other inflammatory arthropathies and correlation with outcome. Clin Exp Rheumatol. 2005;23:185–192
  40. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–2682
  41. Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone. 2003;32:1–7
  42. Abramson SB, Amin A. Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. Rheumatology (Oxford). 2002;41:972–980
  43. Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988;2:706–709
  44. Saidenberg-Kermanac'h N, Corrado A, Lemeiter D, deVernejoul MC, Boissier MC, Cohen-Solal ME. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone. 2004;35:1200–1207
  45. Suematsu A, Tajiri Y, Nakashima T, Taka J, Ochi S, Oda H, et al. Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis. Mod Rheumatol. 2007;17:17–23
  46. Kim MS, Day CJ, Selinger CI, Magno CL, Stephens SR, Morrison NA. MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase (NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption). J Biol Chem. 2006;281:1274–1285
  47. Guler-Yuksel M, Bijsterbosch J, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Hulsmans HM, de Beus WM, et al. Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis. Ann Rheum Dis. 2008;67:823–828
  48. Chopin F, Garnero P, le Henanff A, Debiais F, Daragon A, Roux C, et al. Long term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67:353–357
  49. Pixley JS, Patchin GM. Felty's syndrome. BioDrugs. 1997;7:356–365
  50. Bowman SJ, Hall MA, Panayi GS, Lanchbury JS. T cell receptor alpha-chain and beta-chain junctional region homology in clonal CD3+, CD8+ T lymphocyte expansions in Felty's syndrome. Arthritis Rheum. 1997;40:615–623
  51. Meliconi R, Uguccioni M, Chieco-Bianchi F, Pitzalis C, Bowman S, Facchini A, et al. The role of interleukin-8 and other cytokines in the pathogenesis of Felty's syndrome. Clin Exp Rheumatol. 1995;13:285–291
  52. Sordet C, Gottenberg JE, Hellmich B, Kieffer P, Mariette X, Sibilia J. Lack of efficacy of rituximab in Felty's syndrome. Ann Rheum Dis. 2005;64:332–333
  53. Ghavami A, Genevay S, Fulpius T, Gabay C. Etanercept in treatment of Felty's syndrome. Ann Rheum Dis. 2005;64:1090–1091
  54. del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737–2745
  55. Turesson C, Jarenros A, Jacobsson L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann Rheum Dis. 2004;63:952–955
  56. Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66:70–75
  57. De Pablo P, Dietrich T, Karlson EW. Antioxidants and other novel cardiovascular risk factors in subjects with rheumatoid arthritis in a large population sample. Arthritis Rheum. 2007;57:953–962
  58. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006;144:249–256
  59. Dessein PH, Joffe BI, Singh S. Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R634–R643
  60. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA. 2001;286:2107–2113
  61. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–1772
  62. Gerli R, Sherer Y, Bocci EB, Vaudo G, Moscatelli S, Shoenfeld Y. Precocious atherosclerosis in rheumatoid arthritis: role of traditional and disease-related cardiovascular risk factors. Ann NY Acad Sci. 2007;1108:372–381
  63. Choi HK, Seeger JD. Lipid profiles among US elderly with untreated rheumatoid arthritis—the third National Health and Nutrition Examination Survey. J Rheumatol. 2005;32:2311–2316
  64. Boers M, Nurmohamed MT, Doelman CJ, Lard LR, Verhoeven AC, Voskuyl AE, et al. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:842–845
  65. Allanore Y, Kahan A, Sellam J, Ekindjian OG, Borderie D. Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis. Clin Chim Acta. 2006;365:143–148
  66. Popa C, Netea MG, Radstake T, Van der Meer JW, Stalenhoef AF, van Riel PL, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64:303–305
  67. Seriolo B, Paolino S, Sulli A, Fasciolo D, Cutolo M. Effects of anti-TNF-alpha treatment on lipid profile in patients with active rheumatoid arthritis. Ann NY Acad Sci. 2006;1069:414–419
  68. Tam LS, Tomlinson B, Chu TT, Li TK, Li EK. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1495–1498
  69. van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther. 2006;8:R151
  70. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002;106:2184–2187
  71. Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32:1213–1218
  72. Dixon WG, Watson KD, Lunt M, Hyrich KL, Silman AJ, Symmons DP. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56:2905–2912
  73. Liang KP, Liang KV, Matteson EL, McClelland RL, Christianson TJ, Turesson C. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum. 2006;54:642–648
  74. Gonzalez A, Maradit Kremers H, Crowson CS, Ballman KV, Roger VL, Jacobsen SJ, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-RA patients?. Ann Rheum Dis. 2008;67:64–69
  75. Prada J, Noelle B, Baatz H, Hartmann C, Pleyer U. Tumour necrosis factor alpha and interleukin 6 gene expression in keratocytes from patients with rheumatoid corneal ulcerations. Br J Ophthalmol. 2003;87:548–550
  76. Atchia II, Kidd CE, Bell RW. Rheumatoid arthritis-associated necrotizing scleritis and peripheral ulcerative keratitis treated successfully with infliximab. J Clin Rheumatol. 2006;12:291–293
  77. Fujita M, Igarashi T, Kurai T, Sakane M, Yoshino S, Takahashi H. Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol. 2005;140:808–813
  78. Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. 2005;25:429–435
  79. Turesson C, Matteson EL, Colby TV, Vuk-Pavlovic Z, Vassallo R, Weyand CM, et al. Increased CD4+ T cell infiltrates in rheumatoid arthritis-associated interstitial pneumonitis compared with idiopathic interstitial pneumonitis. Arthritis Rheum. 2005;52:73–79
  80. Atkins SR, Turesson C, Myers JL, Tazelaar HD, Ryu JH, Matteson EL, et al. Morphologic and quantitative assessment of CD20+ B cell infiltrates in rheumatoid arthritis-associated nonspecific interstitial pneumonia and usual interstitial pneumonia. Arthritis Rheum. 2006;54:635–641
  81. Wolfe F, Caplan L, Michaud K. Rheumatoid arthritis treatment and the risk of severe interstitial lung disease. Scand J Rheumatol. 2007;36:172–178
  82. Dixon WG, Watson KD, Lunt M, Hyrich KL. Rheumatoid arthritis, interstitial lung disease, mortality and anti-TNF therapy: results from the BSR Biologics Register (BSRBR). In: ACR/ARHP Annual Scientific Meeting 2007. Boston (MA). November 6-11, 2007;(Abstract)

PII: S0049-0172(08)00135-2

doi: 10.1016/j.semarthrit.2008.08.003

Seminars in Arthritis and Rheumatism
Volume 39, Issue 2 , Pages 132-143 , October 2009

Article Tools

* Image Usage & Resolution