Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Etiology and pathogenesis of rheumatoid vasculitis

Patrick Whelan, MD, PhD
Section Editor
Eric L Matteson, MD, MPH
Deputy Editor
Paul L Romain, MD


Rheumatoid vasculitis (RV) refers to a destructive, inflammatory process that is centered on the blood vessel wall itself. The condition occurs in patients with longstanding, severe rheumatoid arthritis (RA). RV is often associated with substantial potential morbidity, requires intensive immunosuppressive therapy, and leads to a significantly higher mortality than RA itself. Within a given patient with RV, clinical features of both medium- and small-vessel disease may be found. RV leads to necrosis, blood vessel occlusion, and tissue ischemia in a manner that resembles other forms of systemic vasculitis, particularly polyarteritis nodosa (medium-vessel disease) and cutaneous small-vessel vasculitis. (See "Overview of and approach to the vasculitides in adults" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Overview of cutaneous small vessel vasculitis".)

Understanding of the precipitating factors for these extremes of blood vessel inflammation in RA is limited. Although the decreased life expectancy and early cardiovascular mortality in RA are well-recognized, any relationship between atherosclerotic vascular disease leading to thrombosis and RV is dubious, despite many common risk factors for these two RA complications. Atherosclerotic coronary heart disease and its relationship to RA are discussed in detail separately. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management".)

The etiology and pathogenesis of RV are reviewed in this topic. The epidemiology, clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Treatment of rheumatoid vasculitis".)


Rheumatoid vasculitis (RV) has been classified among the forms of vasculitis associated with systemic disease, rather than as a small-, medium-, or variable-vessel form of vasculitis (see "Overview of and approach to the vasculitides in adults"). The first series of patients with RV was published in 1951, describing transmural inflammation of large arterioles and small arteries in 5 of 55 patients (9 percent) who underwent skeletal muscle biopsy [1]. A classification of vasculitis published in 1978 focused on the skin manifestations of RV and placed it as a subcategory of hypersensitivity angiitis associated with immune complex deposition primarily in small venules [2]. Although this type of blood vessel involvement occurs in RV, the most devastating clinical features of the condition stem from vasculitis affecting medium-sized arteries in a manner resembling polyarteritis nodosa. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

Placing RV in any classification of vasculitis is difficult because of the variability both in the size of the vessel involved and in the histologic findings. Three major vasculitis classifications published in the 1990s chose not to address “secondary” forms of vasculitis that occur in patients with known “connective tissue disorders” (systemic autoimmune rheumatic diseases) [3-5]. However, a group of vasculitis experts convened in 2011 for the second International Chapel Hill Consensus Conference updated the previous classification and chose to include four new categories of vasculitis, one of which was “vasculitis associated with systemic disease” [6]. The conference participants were reluctant to broadly divide all the different vasculitic diseases into “primary” and “secondary” forms of vasculitis, due to the expectation that ongoing research might be expected to eventually move certain conditions from the primary into the secondary category as the pathogenesis of these diseases becomes better understood. (See "Overview of and approach to the vasculitides in adults".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Aug 19, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. SOKOLOFF L, WILENS SL, BUNIM JJ. Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 1951; 27:157.
  2. Fauci AS, Haynes B, Katz P. The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations. Ann Intern Med 1978; 89:660.
  3. Calabrese LH, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 1990; 33:1108.
  4. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum 1990; 33:1074.
  5. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187.
  6. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1.
  7. Townend JN, Emery P, Davies MK, Littler WA. Acute aortitis and aortic incompetence due to systemic rheumatological disorders. Int J Cardiol 1991; 33:253.
  8. Kaneko S, Yamashita H, Sugimori Y, et al. Rheumatoid arthritis-associated aortitis: a case report and literature review. Springerplus 2014; 3:509.
  9. SOKOLOFF L, MCCLUSKEY RT, BUNIM JJ. Vascularity of the early subcutaneous nodule of rheumatoid arthritis. AMA Arch Pathol 1953; 55:475.
  10. Myasoedova E, Crowson CS, Turesson C, et al. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a population-based study. J Rheumatol 2011; 38:983.
  11. Watts RA, Mooney J, Lane SE, Scott DG. Rheumatoid vasculitis: becoming extinct? Rheumatology (Oxford) 2004; 43:920.
  12. Makol A, Matteson EL, Warrington KJ. Rheumatoid vasculitis: an update. Curr Opin Rheumatol 2015; 27:63.
  13. Makol A, Crowson CS, Wetter DA, et al. Vasculitis associated with rheumatoid arthritis: a case-control study. Rheumatology (Oxford) 2014; 53:890.
  14. Fujimoto M, Kaku Y, Yamakawa N, et al. Methotrexate-associated EBV-positive vasculitis in the skin: a report of two cases simulating rheumatoid vasculitis. J Cutan Pathol 2016; 43:520.
  15. Shimoura N, Fukunaga A, Nagai H, et al. Epstein-Barr virus-associated methotrexate-induced accelerated rheumatoid nodulosis. Acta Derm Venereol 2015; 95:100.
  16. Yamakawa N, Fujimoto M, Kawabata D, et al. A clinical, pathological, and genetic characterization of methotrexate-associated lymphoproliferative disorders. J Rheumatol 2014; 41:293.
  17. Fujieda M, Tsuruga K, Sato T, et al. Monitoring of Epstein-Barr virus load and killer T cells in patients with juvenile idiopathic arthritis treated with methotrexate or tocilizumab. Mod Rheumatol 2016; :1.
  18. Miceli-Richard C, Gestermann N, Amiel C, et al. Effect of methotrexate and anti-TNF on Epstein-Barr virus T-cell response and viral load in patients with rheumatoid arthritis or spondylarthropathies. Arthritis Res Ther 2009; 11:R77.
  19. EPSTEIN WV, ENGLEMAN EP. The relation of the rheumatoid factor content of serum to clinical neurovascular manifestations of rheumatoid arthritis. Arthritis Rheum 1959; 2:250.
  20. KEMPER JW, BAGGENSTOSS AH, SLOCUMB CH. The relationship of therapy with cortisone to the incidence of vascular lesions in rheumatoid arthritis. Ann Intern Med 1957; 46:831.
  21. Voskuyl AE, Zwinderman AH, Westedt ML, et al. Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study. Ann Rheum Dis 1996; 55:190.
  22. Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004; 31:1955.
  23. Goronzy JJ, Weyand CM. Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol 1994; 6:290.
  24. Perdriger A, Chalès G, Semana G, et al. Role of HLA-DR-DR and DR-DQ associations in the expression of extraarticular manifestations and rheumatoid factor in rheumatoid arthritis. J Rheumatol 1997; 24:1272.
  25. Voskuyl AE, Hazes JM, Schreuder GM, et al. HLA-DRB1, DQA1, and DQB1 genotypes and risk of vasculitis in patients with rheumatoid arthritis. J Rheumatol 1997; 24:852.
  26. Gorman JD, David-Vaudey E, Pai M, et al. Particular HLA-DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis. Arthritis Rheum 2004; 50:3476.
  27. Glass D, Soter NA, Gibson D, et al. Association between HLA and cutaneous necrotizing venulitis. Arthritis Rheum 1976; 19:945.
  28. Hillarby MC, Ollier WE, Davis M, et al. Unusual DQA-DR haplotypes in rheumatoid vasculitis. Br J Rheumatol 1993; 32:93.
  29. Hillarby MC, Clarkson R, Grennan DM, et al. Immunogenetic heterogeneity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. Br J Rheumatol 1991; 30:5.
  30. Struthers GR, Scott DL, Delamere JP, et al. Smoking and rheumatoid vasculitis. Rheumatol Int 1981; 1:145.
  31. Vessey MP, Villard-Mackintosh L, Yeates D. Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception 1987; 35:457.
  32. Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996; 39:732.
  33. Masdottir B, Jónsson T, Manfredsdottir V, et al. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology (Oxford) 2000; 39:1202.
  34. Turesson C, Schaid DJ, Weyand CM, et al. Association of HLA-C3 and smoking with vasculitis in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54:2776.
  35. Padyukov L, Silva C, Stolt P, et al. 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.
  36. del Rincón I, Freeman GL, Haas RW, et al. Relative contribution of cardiovascular risk factors and rheumatoid arthritis clinical manifestations to atherosclerosis. Arthritis Rheum 2005; 52:3413.
  37. Cavagna L, Boffini N, Cagnotto G, et al. Atherosclerosis and rheumatoid arthritis: more than a simple association. Mediators Inflamm 2012; 2012:147354.
  38. Heurkens AH, Hiemstra PS, Lafeber GJ, et al. Anti-endothelial cell antibodies in patients with rheumatoid arthritis complicated by vasculitis. Clin Exp Immunol 1989; 78:7.
  39. van der Zee JM, Heurkens AH, van der Voort EA, et al. Characterization of anti-endothelial antibodies in patients with rheumatoid arthritis complicated by vasculitis. Clin Exp Rheumatol 1991; 9:589.
  40. Belizna C, Tervaert JW. Specificity, pathogenecity, and clinical value of antiendothelial cell antibodies. Semin Arthritis Rheum 1997; 27:98.
  41. Scott DG, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical and laboratory study of 50 cases. Medicine (Baltimore) 1981; 60:288.
  42. Conn DL, McDuffie FC, Dyck PJ. Immunopathologic study of sural nerves in rheumatoid arthritis. Arthritis Rheum 1972; 15:135.
  43. Westedt ML, Daha MR, de Vries E, et al. IgA containing immune complexes in rheumatoid vasculitis and in active rheumatoid disease. J Rheumatol 1985; 12:449.
  44. Westedt ML, Meijer CJ, Vermeer BJ, et al. Rheumatoid arthritis--the clinical significance of histo- and immunopathological abnormalities in normal skin. J Rheumatol 1984; 11:448.
  45. Westedt ML, Daha MR, Baldwin WM 3rd, et al. Serum immune complexes containing IgA appear to predict erosive arthritis in a longitudinal study in rheumatoid arthritis. Ann Rheum Dis 1986; 45:809.
  46. Westedt ML, Herbrink P, Molenaar JL, et al. Rheumatoid factors in rheumatoid arthritis and vasculitis. Rheumatol Int 1985; 5:209.
  47. Lobatto S, Daha MR, Westedt ML, et al. Diminished clearance of soluble aggregates of human immunoglobulin G in patients with rheumatoid arthritis. Scand J Rheumatol 1989; 18:89.
  48. Waxman FJ, Hebert LA, Cosio FG, et al. Differential binding of immunoglobulin A and immunoglobulin G1 immune complexes to primate erythrocytes in vivo. Immunoglobulin A immune complexes bind less well to erythrocytes and are preferentially deposited in glomeruli. J Clin Invest 1986; 77:82.
  49. Heurkens AH, Westedt ML, Breedveld FC, et al. Uptake and degradation of soluble aggregates of IgG by monocytes of patients with rheumatoid arthritis: relation to disease activity. Ann Rheum Dis 1991; 50:284.
  50. Heurkens AH, Breedveld FC, Keur CV, et al. Degradation of aggregates of activated C3 (C3b) by monocytes of patients with rheumatoid arthritis is related to vasculitis. Clin Exp Immunol 1990; 80:177.
  51. Siegert CE, Daha MR, van der Voort EA, Breedveld FC. IgG and IgA antibodies to the collagen-like region of C1q in rheumatoid vasculitis. Arthritis Rheum 1990; 33:1646.
  52. Yen JH, Moore BE, Nakajima T, et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med 2001; 193:1159.
  53. Tesfamariam B, DeFelice AF. Endothelial injury in the initiation and progression of vascular disorders. Vascul Pharmacol 2007; 46:229.
  54. Di Comite G, Rossi CM, Marinosci A, et al. Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation. J Leukoc Biol 2009; 85:81.
  55. Chen LF, Mo YQ, Ma JD, et al. Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis. Mediators Inflamm 2014; 2014:635293.