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Vasculitis Unlimited in Rheumatoid Arthritis
VIEWS AND REVIEWS IN VASCULAR MEDICINE AND BIOLOGY
Vasculitis Unlimited in Rheumatoid Arthritis: An Illustrated Review J. T. Lie, MD Department of Pathology, University of California Davis Medical Center, Sacramento, California
11 Rheumatoid arthritis has a multitude of extra-articular manifestations, of which systemic vasculitis is a clinically significant co-morbidity and co-mortality determinant in the prognosis of the disease. Rheumatoid vasculitis may occur in the early stage of the disease but, more commonly, in patients who have had seropositive rheumatoid arthritis for 10 years or longer. Rheumatoid vasculitis has a wide variety of histopathologic expressions and it may affect blood vessels of all sizes (from vasa nervorum or vasa vasorum to the aorta; and occasionally veins and venules). The diagnosis ideally requires biopsy or autopsy tissue confirmation, which is discussed and illustrated in this review. Cardiovasc Pathol 1998;7:191–204 © 1998 by Elsevier Science Inc.
Rheumatoid Arthritis and Rheumatoid Vasculitis Rheumatoid arthritis is an immune-mediated, chronic, nonsuppurative, inflammatory polyarthritis affecting mainly the peripheral synovial joints, usually in a symmetrical fashion, with a prolonged clinical course of exacerbations and remissions, and often accompanied by signs and symptoms of a systemic disease. The concept of rheumatoid arthritis as a systemic disease began in 1948 when Bauer and Clark (1) first described extra-articular manifestations of rheumatoid arthritis and in the same year, Ellman and Ball (2) first introduced the term “rheumatoid disease.” Rheumatoid arthritis occurs worldwide. The most often cited prevalence is 1% in the adult populations, but there is a wide variation of the reported rates from different ethnic groups. The highest prevalence has been found among some Native American populations and lowest in certain Asian and African populations (3). The age distribution of rheumatoid arthritis is unimodal with a peak incidence between the 4th and 6th decades of life; and women are two to three times more likely to develop the disease than men. Compared with the age and gender matched control populations,
Manuscript received October 29, 1997; accepted November 20, 1997. At time of publication Dr. J. T. Lie is deceased. Cardiovascular Pathology Vol. 7, No. 4, July/August 1998:191–204 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
the mortality rates are increased at least two-fold in rheumatoid arthritis patients; and the higher rates are linked to clinical severity of the disease and particularly among patients whose disease began before 50 years of age. While the articular lesions of rheumatoid arthritis are disabling, the major cause of morbidity and mortality can be attributed largely to extra-articular manifestations of the disease; which tend to occur in patients who are seropositive with higher rheumatoid factor titers and in whom both the severity and duration of the disease are greater (3,4). Systemic vasculitis is a clinically significant co-morbidity and co-mortality determinant in the prognosis of rheumatoid arthritis. Rheumatoid vasculitis may occur early but, more commonly, in patients who have had seropositive rheumatoid arthritis for 10 years or longer. A high prevalence of the HLA-DR4 allele in rheumatoid vasculitis when compared with uncomplicated rheumatoid arthritis and the control patient populations implicates an immunogenetic predisposition (4–6). This is the centennial year of the first known report of rheumatoid vasculitis. Bannatyne, in 1898 (7), described involvement of the peripheral nerves in rheumatoid arthritis with microscopic changes in the vasa nervorum. Small- and large-vessel rheumatoid vasculitis was a popular subject review in the literature from 1940s through 1960s (8–18) but, save isolated case reports, is a topic seldom discussed in the past 40 years (19–24).
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Clinical experience suggests focal cutaneous lesions and isolated distal sensory neuropathy are not necessarily indicative of a poor prognosis, but multiple organ and visceral involvement is predictive of increased morbidity and decreased actuarial survival of the patients. Patients who develop rheumatoid vasculitis often have never taken disease-modifying drugs or have tolerated these drugs poorly (4,19,21). In patients with rheumatoid vasculitis, the most prominent clinical features are sensory neuropathy, leg ulcers, and skin rash or purpura; commonly associated with an elevated erythrocyte sedimentation rate, rheumatoid factor titer of .1:2560, cryoglobulinemia or detectable IgG- and C3-containing circulating immune complexes. and abnormal peripheral nerve conduction velocity in electromyography tests (20). Depending on the organ tissue affected, the prevalence of rheumatoid vasculitis ranges from 10% to 40% (4,5,19– 23). Rheumatoid vasculitis is a systemic vasculitis and it has literally unlimited clinical manifestations because blood vessels of all sizes may be affected (from vasa nervorum or vasa vasorum to the aorta, and occasionally veins and venules). Its histopathologic expressions in biopsy and au-
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topsy specimens include active and healed polyarteritis-type necrotizing vasculitis, lymphocytic vasculitis, granulomatous vasculitis, or a combination thereof (24). Some of the more notable catastrophic complications of rheumatoid vasculitis include aortitis, aortic aneurysms, and acute aortic insufficiency (23); ruptured visceral arterial aneurysms with hemoperitoneum, bowel infarction or perforation (25,26); and coronary arteritis with myocardial infarction (27–30).
Diagnosis The diagnosis of rheumatoid vasculitis, other than at autopsy, could be and is frequently determined from clinical, laboratory, and angiographic examinations (4); biopsy confirmation is necessary and strongly recommended before subjecting the patient to immunosuppressive therapy. There are mimickers of vasculitis for which immunosuppressive therapy not only is ineffectual but also may cause catastrophic complications (31). Selected biopsy sites may be the symptomatically involved organs or, in their absence, any of the more accessible tissues, such as the skeletal muscle, peripheral nerve,
Figure 1. (A) A fortuitous capture of a solitary artery with necrotizing vasculitis (arrow) at the edge of a 9 3 6 mm positive muscle biopsy. Note the rest of the biopsy is absolutely bland and normal (the bar measures 1 mm). (B) Close-up view of the focal segmental necrotizing vasculitis. (Hematoxylin-eosin: A 316; B 3160.)
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and rectum, probably in that order of preference. In the vast majority of cases, light microscopy of multiple hematoxylin-eosin and elastin stain sections would be all that is necessary. Immunohistochemical study of the muscle biopsy (for detecting enzymes or immune complexes) and ultrastructural study of the nerve biopsy (for detecting axonal degeneration) are optional diagnostic procedures (32). In random or “blind” biopsies, the gastrocnemius muscle and sural nerve are traditionally chosen. Alternatively, the superficial branch of the peroneal nerve and the peroneal brevis muscle may be conveniently biopsied at the same single procedure with comparably satisfactory results (33).
Small-Vessel Vasculitis Not unlike idiopathic polyarteritis, rheumatoid vasculitis, wherever it occurs, tends to be a focal segmental lesion and, therefore, an isolated negative biopsy does not prove the absence of the disease; only a positive biopsy is confirmatory. Serendipity plays an unexpectedly important role in the procurement of a positive biopsy. Time and again one finds a solitary lesion located at the very edge of an adequate-sized (.9 3 6 mm) biopsy (Figure 1). Unbeknown to the pathol-
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ogist, such a lesion could easily have been “trimmed off” before tissue processing, or have just simply “floated off” during mounting and staining procedures of the histologic sections. Clinical involvement of the gastrointestinal tract and heart in rheumatoid vasculitis occurs in 10%–15% of the patients and may be the first manifestation of the disease (5,21,27–29,34–36). The resulting ischemic bowel and ischemic heart disease may be clinically silent or masked in elderly, debilitated, and immunosuppressed patients who also regularly take analgesics for aches and pains, with the inevitable high mortality rates among the reported series of cases (5,22,34). Healing or healed rheumatoid vasculitis in the gastrointestinal tract may masquerade as idiopathic mesenteric arterial intimal proliferative and obstructive disease causing intestinal infarction (37–40). In rheumatoid vasculitis, as in idiopathic polyarteritis, the same assortment of histopathologic changes may be observed in different segments of the same artery and in different arteries of the same specimen (41). These changes include, in the same or separate biopsies of the patient: focal segmental necrotizing vasculitis (Figure 1); diffuse or focal segmental necrotizing vasculitis and granulomatous vascu-
Figure 2. A classic diffuse polyarteritis-type necrotizing vasculitis in a muscle biopsy (A) side-byside with a granulomatous vasculitis in different part of the same biopsy (B). (Hematoxylin-eosin: A 3160; B 3400.)
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Figure 3. A classic diffuse polyarteritis-type necrotizing vasculitis in the kidney (A) coexisting with a granulomatous vasculitis in the lung (B) of the same rheumatoid arthritis patient who had systemic vasculitis. (Hematoxylin-eosin: A 3160; B 3400.)
litis (Figures 2–4); normal unaffected artery coexisting with lymphocytic vasculitis and vasculitis with fibrinoid necrosis (Figure 5); and necrotizing vasculitis coexisting with healing or healed vasculitis (Figures 6 and 7). In rheumatoid arthritis patients who died of myocardial infarction or myocarditis, the heart may show granulomatous coronary arteritis (Figure 8), epicardial and intramyocardial necrotizing vasculitis (Figure 9), or coronary arteritis coexisting with granulomatous myocarditis (Figure 10). Cerebral (42) or pulmonary (43) vascular disease in rheumatoid arthritis patients has rarely been described in the literature.
Large-Vessel Vasculitis Mallory was credited with the first pathologic description of aortitis in rheumatoid arthritis in 1936 (44), since that time fewer than 10 major publications appeared sporadically in the literature describing cardiovascular manifestations of rheumatoid arthritis (27–30,34,36,45,46). Clark et
al., in 1957 (45), described pathologic changes of the aortic valves and ascending aorta in 22 patients; Zvaifler and Weintraub in 1963 (46) described five patients with aortic regurgitation, of whom two had aortitis; and another 26 years elapsed before the recent report by Gravallese et al. in 1989 (23), of 10 patients with rheumatoid aortitis. Virtually all cases of rheumatoid aortitis occur in the aneurysmal ascending aorta associated with aortic valve insufficiency (Figure 11). The tell-tale rheumatoid necrobiotic nodules in aortitis may be found intramurally (Figure 11B), in the intima or adventitia (Figure 12). About half of the patients have aortic valvulitis, which may be floridly granulomatous or with diffuse lymphocytic infiltrate and necrobiotic nodules (Figure 13). In rheumatoid aortitis with intimal fibrosis, histologic examination of multiple sections of surgically resected arterial walls may reveal sequentially progressive intimal proliferation with increasingly more profuse lymphocytic infiltrate—a heretofore undescribed feature of, though not necessarily specific for, rheumatoid vasculitis that may be dubbed “intimitis” (Figure 14).
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Figure 4. (A) Mesenteric artery rheumatoid vasculitis that shows segmental changes from being granulomatous (boxed area) to necrotizing (arrows); the boxed area is shown close-up in (B). (Hematoxylin-eosin: A 364; B 3160.)
Conclusion
2. Ellman P, Ball RE. Rheumatoid disease with joint and pulmonary manifestations. Br Med J 1948;2:816–820.
Vasculitis in rheumatoid arthritis is indeed unlimited in both the histopathologic variations and the vascular beds affected. The small- and medium-sized-vessel vasculitis is akin to idiopathic polyarteritis and the large-vessel vasculitis is typified by granulomatous or lymphocytic aortitis with variable intimal proliferation. Rheumatoid aortitis characteristically occurs in the aneurysmal ascending aorta and often is associated with aortic insufficiency. Aortic valvulitis, when present, may show granulomatous or lymphocytic infiltrate and necrobiotic nodules. Clinicoangiographic diagnosis of rheumatoid vasculitis should be verified with biopsies whenever possible. Systematic sampling of the biopsy or autopsy material, and a meticulous microscopy that leaves no parts of the tissue sections unexamined, are essential for not overlooking evidence of rheumatoid vasculitis.
10. Ball J. Rheumatoid arthritis and polyarteritis nodosa. Ann Rheum Dis 1954;13:277–290.
Note: Figures 5–14 appear on following pages.
11. Sokoloff L, Wilens SL, Bunim JJ. Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 1951;27:157–168.
3. Silman AJ, Hochberg MC. Epidemiology of the Rheumatic Diseases. Oxford: Oxford University Press, 1993:7–68. 4. Vollertsen RS, Conn DL. Vasculitis associated with rheumatoid arthritis. Rheum Dis Clin North Am 1990;16:445–461. 5. Scott DGI, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical and laboratory study of 50 cases. Medicine 1981;60:288–297. 6. Farrel JB, Person DA, Rossen RD, Lidsky MD. Role of immune complexes in rheumatoid polyarteritis. Ann Rheum Dis 1979;38:390–393. 7. Bannatyne GA. Rheumatoid Arthritis: Its Pathology, Morbid Anatomy, and Treatment, 2nd Ed. Bristol: John Wright, 1898:73. 8. Pagel W. Polyarteritis nodosa and the “rheumatic” diseases. J Clin Pathol 1951;4:137–157. 9. Cruickshank B. The arteritis of rheumatoid arthritis. Ann Rheum Dis 1954;13:136–146.
12. Sokoloff L, Bunim JJ. Vascular lesions in rheumatoid arthritis. J Chron Dis 1957;5:668–687.
References 1. Bauer W, Clark WS. The systemic manifestations of rheumatoid arthritis. Trans Assoc Am Physcns 1948;61:339–343.
13. Clark WS, Kulka P, Bauer W. Rheumatoid arthritis and aortic regurgitation. Am J Med 1957;22:580–592. 14. Bywaters EGL. Peripheral vascular obstruction in rheumatoid arthritis
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Figure 5. (A) Positive muscle biopsy with a solitary lymphocytic vasculitis right at the edge of the tissue section (large arrow) that also has normal unaffected arteries (small arrow). (B) Close-up view of the lymphocytic vasculitis. (C) Coexisting mesenteric vasculitis with fibrinoid necrosis. (Hematoxylin-eosin: A 316; B and C 3400.)
and its relationship to other vascular lesions. Ann Rheum Dis 1957;16:84–103. 15. Bywaters EGL, Scott JT. The natural history of vascular lesions in rheumatoid arthritis. J Chron Dis 1963;16:905–914.
24.
16. Schmid FR, Cooper NS, Ziff M, McEwen C. Arteritis in rheumatoid arthritis. Am J Med 1961;30:56–83.
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17. Wilkinson M, Torrance WN. Clinical background of rheumatoid vascular disease. Ann Rheum Dis 1967;26:475–480.
26.
18. Morgan ES, Cass RM, Jacox RF, et al. A study of the relation of seronegative and seropositive rheumatoid arthritis to each other and to necrotizing vasculitis. Am J Med 1969;47:23–35.
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19. Panush RS, Katz P, Longley S, et al. Rheumatoid vasculitis: diagnostic and therapeutic decisions. Clin Rheum Dis 1983;2:321–330.
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20. Schneider HA, Yonker RA, Katz P, et al. Rheumatoid vasculitis: experience with 13 patients and review of the literature. Semin Arthritis Rheum 1985;14:280–286.
29.
21. Vollertsen RS, Conn DL, Ballard DJ, et al. Rheumatoid vasculitis: survival and associated risk factors. Medicine 1986;65:365–375.
30. 31.
22. Geirsson AJ, Sturfelt G, Truedsson L. Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications. Ann Rheum Dis 1987;46:727–733. 23. Gravallese EM, Corson JM, Coblyn JS, et al. Rheumatoid aortitis: a
32.
rarely recognized but clinically significant entity. Medicine 1989; 68:95–106. Lie JT. Biopsy Diagnosis in Rheumatic Diseases. New York: IgakuShoin, 1997;13–23. Moreland L, DiBartolomeo A, Brick. Rheumatoid vasculitis with intrarenal aneurysm formation. J Rheumatol 1988;15:845–849. Achkar AA, Stanson AW, Johnson CM, et al. Rheumatoid vasculitis manifesting as intra-abdominal hemorrhage. Mayo Clin Proc 1995; 70:565–569. Lebowitz WB. The heart in rheumatoid arthritis (rheumatic disease): a clinical and pathological study of 62 cases. Ann Intern Med 1963; 58:102–123. Weintraub AM, Zvaifler NJ. The occurrence of valvular and myocardial disease in patients with chronic joint deformity. Am J Med 1963;35:145–162. Sokoloff L. Cardiac involvement in rheumatoid arthritis and allied disorders: current concepts. Mod Conc Cardiovasc Dis 1964;33:847–850. Lie JT. Coronary vasculitis. Arch Pathol Lab Med 1987;111:224–233. Lie JT. Systemic, cerebral, and pulmonary segmental mediolytic arteriopathy: villainous masqueraders of vasculitis. Cardiovasc Pathol 1996;5:305–314. Lie JT. Biopsy diagnosis of systemic vasculitis. Baillière Clin Rheumatol 1997;11:219–236.
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Figure 6. Unsuspected fatal pancreatitis in rheumatoid arthritis. Autopsy shows pancreas with acute (A), healing (B), and healed (C) vasculitis. (Hematoxylin-eosin: A 3160; B and C 3400.)
33. Puéchal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis: a clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995;38: 1618–1629. 34. Barker A. Rheumatoid arthritis and rheumatoid heart disease. NZ Med J 1971;73:14–18. 35. Voyles WF, Searles RP, Bankhurst AD. Myocardial infarction caused by rheumatoid vasculitis. Arthritis Rheum 1980;23:860–863. 36. Lie JT. Rheumatoid arthritis and heart disease. Prim Cardiol 1982; 10(10):137–152. 37. Aboumrad MH, Fine G, Horn RC Jr. Intimal hyperplasia of small mesenteric arteries. Arch Pathol Lab Med 1963;75:196–200. 38. McGregor DH, Pierce GE, Thomas JH, Tilzer LL. Obstructive lesions of distal mesenteric arteries. Arch Pathol Lab Med 1980;104:79–83. 39. McCurley TL, Collins RD. Intestinal infarction in rheumatoid arthritis. Arch Pathol Lab Med 1984;108:125–128.
40. Lie JT. Gastrointestinal vasculitis and vasculitis associated with gastrointestinal diseases. Cardiovasc Pathol 1998;7(2):109–118. 41. Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21:883–909. 42. Ramos M, Mandybur TI. Cerebral vasculitis in rheumatoid arthritis. Arch Neurol 1975;32:271–275. 43. Cerventes-Perez P, Toro-Perez AH, Rodriquez-Jurado P. Pulmonary involvement in rheumatoid arthritis. JAMA 1980;243:915–919. 44. Mallory BT. Case records of the Massachusetts General Hospital: cases 22141,22142. N Engl J Med 1936;214:690–698. 45. Clark WS, Kulka P, Bauer W. Rheumatoid arthritis with aortic regurgitation. Am J Med 1957;22:580–592. 46. Zvaifler NJ, Weintraub AM. Aortitis and aortic insufficiency in the chronic rheumatic disorders: a reappraisal. Arthritis Rheum 1963;6: 241–245.
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Figure 7. Intestinal necrotizing vasculitis (A) coexisting with healing vasculitis (B) in resected gangrenous small bowel. (Hematoxylin-eosin: A 3160; B 3400.)
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Figure 8. (A) Granulomatous coronary arteritis with intramural rheumatoid nodules, one of which (boxed area) is shown close-up in (B). (Hematoxylin-eosin: A 340; B 3160.)
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Figure 9. Necrotizing vasculitis of epicardial (A) and intramyocardial (B) coronary arteries in rheumatoid arthritis. (Hematoxylin-eosin: A 340; B 3160.)
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Figure 10. (A) Granulomatous coronary arteritis with intramural rheumatoid nodule (arrows) coexisting with granulomatous myocarditis (B). (Hematoxylin-eosin: A 364; B 3400.)
Figure 11. (A) External view of aneurysmal ascending aorta (AA) with aortic regurgitation in a rheumatoid arthritis patient who died of congestive heart failure. (B) The aorta at autopsy showed granulomatous aortitis with intramural necrobiotic nodules (NN). (Hematoxylin-eosin: B 3160.)
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Figure 12. Rheumatoid aortitis with subendothelial (arrow) intimal (A) and adventitial (B) necrobiotic nodules in different parts of the same aorta. (Hematoxylin-eosin: A and B 3160.)
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Figure 13. Aortic valvulitis in rheumatoid arthritis: (A) one with florid granulomatous infiltrate containing giant cells and (B) another with diffuse lymphocytic infiltrate and necrobiotic nodules (arrows). (Hematoxylin-eosin: A and B 3160.)
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Figure 14. Progressive intimal thickening (double-headed arrows) corresponding with increasingly more intense lymphocytic infiltrates in rheumatoid aortitis is shown in (A), (B), and (C); the granulomatous aortitis is shown in (D). (Hematoxylin-eosin: all 3160.)
Vasculitis Unlimited in Rheumatoid Arthritis: An Illustrated Review J. T. Lie, MD Department of Pathology, University of California Davis Medical Center, Sacramento, California
11 Rheumatoid arthritis has a multitude of extra-articular manifestations, of which systemic vasculitis is a clinically significant co-morbidity and co-mortality determinant in the prognosis of the disease. Rheumatoid vasculitis may occur in the early stage of the disease but, more commonly, in patients who have had seropositive rheumatoid arthritis for 10 years or longer. Rheumatoid vasculitis has a wide variety of histopathologic expressions and it may affect blood vessels of all sizes (from vasa nervorum or vasa vasorum to the aorta; and occasionally veins and venules). The diagnosis ideally requires biopsy or autopsy tissue confirmation, which is discussed and illustrated in this review. Cardiovasc Pathol 1998;7:191–204 © 1998 by Elsevier Science Inc.
Rheumatoid Arthritis and Rheumatoid Vasculitis Rheumatoid arthritis is an immune-mediated, chronic, nonsuppurative, inflammatory polyarthritis affecting mainly the peripheral synovial joints, usually in a symmetrical fashion, with a prolonged clinical course of exacerbations and remissions, and often accompanied by signs and symptoms of a systemic disease. The concept of rheumatoid arthritis as a systemic disease began in 1948 when Bauer and Clark (1) first described extra-articular manifestations of rheumatoid arthritis and in the same year, Ellman and Ball (2) first introduced the term “rheumatoid disease.” Rheumatoid arthritis occurs worldwide. The most often cited prevalence is 1% in the adult populations, but there is a wide variation of the reported rates from different ethnic groups. The highest prevalence has been found among some Native American populations and lowest in certain Asian and African populations (3). The age distribution of rheumatoid arthritis is unimodal with a peak incidence between the 4th and 6th decades of life; and women are two to three times more likely to develop the disease than men. Compared with the age and gender matched control populations,
Manuscript received October 29, 1997; accepted November 20, 1997. At time of publication Dr. J. T. Lie is deceased. Cardiovascular Pathology Vol. 7, No. 4, July/August 1998:191–204 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
the mortality rates are increased at least two-fold in rheumatoid arthritis patients; and the higher rates are linked to clinical severity of the disease and particularly among patients whose disease began before 50 years of age. While the articular lesions of rheumatoid arthritis are disabling, the major cause of morbidity and mortality can be attributed largely to extra-articular manifestations of the disease; which tend to occur in patients who are seropositive with higher rheumatoid factor titers and in whom both the severity and duration of the disease are greater (3,4). Systemic vasculitis is a clinically significant co-morbidity and co-mortality determinant in the prognosis of rheumatoid arthritis. Rheumatoid vasculitis may occur early but, more commonly, in patients who have had seropositive rheumatoid arthritis for 10 years or longer. A high prevalence of the HLA-DR4 allele in rheumatoid vasculitis when compared with uncomplicated rheumatoid arthritis and the control patient populations implicates an immunogenetic predisposition (4–6). This is the centennial year of the first known report of rheumatoid vasculitis. Bannatyne, in 1898 (7), described involvement of the peripheral nerves in rheumatoid arthritis with microscopic changes in the vasa nervorum. Small- and large-vessel rheumatoid vasculitis was a popular subject review in the literature from 1940s through 1960s (8–18) but, save isolated case reports, is a topic seldom discussed in the past 40 years (19–24).
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Clinical experience suggests focal cutaneous lesions and isolated distal sensory neuropathy are not necessarily indicative of a poor prognosis, but multiple organ and visceral involvement is predictive of increased morbidity and decreased actuarial survival of the patients. Patients who develop rheumatoid vasculitis often have never taken disease-modifying drugs or have tolerated these drugs poorly (4,19,21). In patients with rheumatoid vasculitis, the most prominent clinical features are sensory neuropathy, leg ulcers, and skin rash or purpura; commonly associated with an elevated erythrocyte sedimentation rate, rheumatoid factor titer of .1:2560, cryoglobulinemia or detectable IgG- and C3-containing circulating immune complexes. and abnormal peripheral nerve conduction velocity in electromyography tests (20). Depending on the organ tissue affected, the prevalence of rheumatoid vasculitis ranges from 10% to 40% (4,5,19– 23). Rheumatoid vasculitis is a systemic vasculitis and it has literally unlimited clinical manifestations because blood vessels of all sizes may be affected (from vasa nervorum or vasa vasorum to the aorta, and occasionally veins and venules). Its histopathologic expressions in biopsy and au-
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topsy specimens include active and healed polyarteritis-type necrotizing vasculitis, lymphocytic vasculitis, granulomatous vasculitis, or a combination thereof (24). Some of the more notable catastrophic complications of rheumatoid vasculitis include aortitis, aortic aneurysms, and acute aortic insufficiency (23); ruptured visceral arterial aneurysms with hemoperitoneum, bowel infarction or perforation (25,26); and coronary arteritis with myocardial infarction (27–30).
Diagnosis The diagnosis of rheumatoid vasculitis, other than at autopsy, could be and is frequently determined from clinical, laboratory, and angiographic examinations (4); biopsy confirmation is necessary and strongly recommended before subjecting the patient to immunosuppressive therapy. There are mimickers of vasculitis for which immunosuppressive therapy not only is ineffectual but also may cause catastrophic complications (31). Selected biopsy sites may be the symptomatically involved organs or, in their absence, any of the more accessible tissues, such as the skeletal muscle, peripheral nerve,
Figure 1. (A) A fortuitous capture of a solitary artery with necrotizing vasculitis (arrow) at the edge of a 9 3 6 mm positive muscle biopsy. Note the rest of the biopsy is absolutely bland and normal (the bar measures 1 mm). (B) Close-up view of the focal segmental necrotizing vasculitis. (Hematoxylin-eosin: A 316; B 3160.)
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and rectum, probably in that order of preference. In the vast majority of cases, light microscopy of multiple hematoxylin-eosin and elastin stain sections would be all that is necessary. Immunohistochemical study of the muscle biopsy (for detecting enzymes or immune complexes) and ultrastructural study of the nerve biopsy (for detecting axonal degeneration) are optional diagnostic procedures (32). In random or “blind” biopsies, the gastrocnemius muscle and sural nerve are traditionally chosen. Alternatively, the superficial branch of the peroneal nerve and the peroneal brevis muscle may be conveniently biopsied at the same single procedure with comparably satisfactory results (33).
Small-Vessel Vasculitis Not unlike idiopathic polyarteritis, rheumatoid vasculitis, wherever it occurs, tends to be a focal segmental lesion and, therefore, an isolated negative biopsy does not prove the absence of the disease; only a positive biopsy is confirmatory. Serendipity plays an unexpectedly important role in the procurement of a positive biopsy. Time and again one finds a solitary lesion located at the very edge of an adequate-sized (.9 3 6 mm) biopsy (Figure 1). Unbeknown to the pathol-
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ogist, such a lesion could easily have been “trimmed off” before tissue processing, or have just simply “floated off” during mounting and staining procedures of the histologic sections. Clinical involvement of the gastrointestinal tract and heart in rheumatoid vasculitis occurs in 10%–15% of the patients and may be the first manifestation of the disease (5,21,27–29,34–36). The resulting ischemic bowel and ischemic heart disease may be clinically silent or masked in elderly, debilitated, and immunosuppressed patients who also regularly take analgesics for aches and pains, with the inevitable high mortality rates among the reported series of cases (5,22,34). Healing or healed rheumatoid vasculitis in the gastrointestinal tract may masquerade as idiopathic mesenteric arterial intimal proliferative and obstructive disease causing intestinal infarction (37–40). In rheumatoid vasculitis, as in idiopathic polyarteritis, the same assortment of histopathologic changes may be observed in different segments of the same artery and in different arteries of the same specimen (41). These changes include, in the same or separate biopsies of the patient: focal segmental necrotizing vasculitis (Figure 1); diffuse or focal segmental necrotizing vasculitis and granulomatous vascu-
Figure 2. A classic diffuse polyarteritis-type necrotizing vasculitis in a muscle biopsy (A) side-byside with a granulomatous vasculitis in different part of the same biopsy (B). (Hematoxylin-eosin: A 3160; B 3400.)
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Figure 3. A classic diffuse polyarteritis-type necrotizing vasculitis in the kidney (A) coexisting with a granulomatous vasculitis in the lung (B) of the same rheumatoid arthritis patient who had systemic vasculitis. (Hematoxylin-eosin: A 3160; B 3400.)
litis (Figures 2–4); normal unaffected artery coexisting with lymphocytic vasculitis and vasculitis with fibrinoid necrosis (Figure 5); and necrotizing vasculitis coexisting with healing or healed vasculitis (Figures 6 and 7). In rheumatoid arthritis patients who died of myocardial infarction or myocarditis, the heart may show granulomatous coronary arteritis (Figure 8), epicardial and intramyocardial necrotizing vasculitis (Figure 9), or coronary arteritis coexisting with granulomatous myocarditis (Figure 10). Cerebral (42) or pulmonary (43) vascular disease in rheumatoid arthritis patients has rarely been described in the literature.
Large-Vessel Vasculitis Mallory was credited with the first pathologic description of aortitis in rheumatoid arthritis in 1936 (44), since that time fewer than 10 major publications appeared sporadically in the literature describing cardiovascular manifestations of rheumatoid arthritis (27–30,34,36,45,46). Clark et
al., in 1957 (45), described pathologic changes of the aortic valves and ascending aorta in 22 patients; Zvaifler and Weintraub in 1963 (46) described five patients with aortic regurgitation, of whom two had aortitis; and another 26 years elapsed before the recent report by Gravallese et al. in 1989 (23), of 10 patients with rheumatoid aortitis. Virtually all cases of rheumatoid aortitis occur in the aneurysmal ascending aorta associated with aortic valve insufficiency (Figure 11). The tell-tale rheumatoid necrobiotic nodules in aortitis may be found intramurally (Figure 11B), in the intima or adventitia (Figure 12). About half of the patients have aortic valvulitis, which may be floridly granulomatous or with diffuse lymphocytic infiltrate and necrobiotic nodules (Figure 13). In rheumatoid aortitis with intimal fibrosis, histologic examination of multiple sections of surgically resected arterial walls may reveal sequentially progressive intimal proliferation with increasingly more profuse lymphocytic infiltrate—a heretofore undescribed feature of, though not necessarily specific for, rheumatoid vasculitis that may be dubbed “intimitis” (Figure 14).
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Figure 4. (A) Mesenteric artery rheumatoid vasculitis that shows segmental changes from being granulomatous (boxed area) to necrotizing (arrows); the boxed area is shown close-up in (B). (Hematoxylin-eosin: A 364; B 3160.)
Conclusion
2. Ellman P, Ball RE. Rheumatoid disease with joint and pulmonary manifestations. Br Med J 1948;2:816–820.
Vasculitis in rheumatoid arthritis is indeed unlimited in both the histopathologic variations and the vascular beds affected. The small- and medium-sized-vessel vasculitis is akin to idiopathic polyarteritis and the large-vessel vasculitis is typified by granulomatous or lymphocytic aortitis with variable intimal proliferation. Rheumatoid aortitis characteristically occurs in the aneurysmal ascending aorta and often is associated with aortic insufficiency. Aortic valvulitis, when present, may show granulomatous or lymphocytic infiltrate and necrobiotic nodules. Clinicoangiographic diagnosis of rheumatoid vasculitis should be verified with biopsies whenever possible. Systematic sampling of the biopsy or autopsy material, and a meticulous microscopy that leaves no parts of the tissue sections unexamined, are essential for not overlooking evidence of rheumatoid vasculitis.
10. Ball J. Rheumatoid arthritis and polyarteritis nodosa. Ann Rheum Dis 1954;13:277–290.
Note: Figures 5–14 appear on following pages.
11. Sokoloff L, Wilens SL, Bunim JJ. Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 1951;27:157–168.
3. Silman AJ, Hochberg MC. Epidemiology of the Rheumatic Diseases. Oxford: Oxford University Press, 1993:7–68. 4. Vollertsen RS, Conn DL. Vasculitis associated with rheumatoid arthritis. Rheum Dis Clin North Am 1990;16:445–461. 5. Scott DGI, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical and laboratory study of 50 cases. Medicine 1981;60:288–297. 6. Farrel JB, Person DA, Rossen RD, Lidsky MD. Role of immune complexes in rheumatoid polyarteritis. Ann Rheum Dis 1979;38:390–393. 7. Bannatyne GA. Rheumatoid Arthritis: Its Pathology, Morbid Anatomy, and Treatment, 2nd Ed. Bristol: John Wright, 1898:73. 8. Pagel W. Polyarteritis nodosa and the “rheumatic” diseases. J Clin Pathol 1951;4:137–157. 9. Cruickshank B. The arteritis of rheumatoid arthritis. Ann Rheum Dis 1954;13:136–146.
12. Sokoloff L, Bunim JJ. Vascular lesions in rheumatoid arthritis. J Chron Dis 1957;5:668–687.
References 1. Bauer W, Clark WS. The systemic manifestations of rheumatoid arthritis. Trans Assoc Am Physcns 1948;61:339–343.
13. Clark WS, Kulka P, Bauer W. Rheumatoid arthritis and aortic regurgitation. Am J Med 1957;22:580–592. 14. Bywaters EGL. Peripheral vascular obstruction in rheumatoid arthritis
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Figure 5. (A) Positive muscle biopsy with a solitary lymphocytic vasculitis right at the edge of the tissue section (large arrow) that also has normal unaffected arteries (small arrow). (B) Close-up view of the lymphocytic vasculitis. (C) Coexisting mesenteric vasculitis with fibrinoid necrosis. (Hematoxylin-eosin: A 316; B and C 3400.)
and its relationship to other vascular lesions. Ann Rheum Dis 1957;16:84–103. 15. Bywaters EGL, Scott JT. The natural history of vascular lesions in rheumatoid arthritis. J Chron Dis 1963;16:905–914.
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16. Schmid FR, Cooper NS, Ziff M, McEwen C. Arteritis in rheumatoid arthritis. Am J Med 1961;30:56–83.
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17. Wilkinson M, Torrance WN. Clinical background of rheumatoid vascular disease. Ann Rheum Dis 1967;26:475–480.
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18. Morgan ES, Cass RM, Jacox RF, et al. A study of the relation of seronegative and seropositive rheumatoid arthritis to each other and to necrotizing vasculitis. Am J Med 1969;47:23–35.
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22. Geirsson AJ, Sturfelt G, Truedsson L. Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications. Ann Rheum Dis 1987;46:727–733. 23. Gravallese EM, Corson JM, Coblyn JS, et al. Rheumatoid aortitis: a
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rarely recognized but clinically significant entity. Medicine 1989; 68:95–106. Lie JT. Biopsy Diagnosis in Rheumatic Diseases. New York: IgakuShoin, 1997;13–23. Moreland L, DiBartolomeo A, Brick. Rheumatoid vasculitis with intrarenal aneurysm formation. J Rheumatol 1988;15:845–849. Achkar AA, Stanson AW, Johnson CM, et al. Rheumatoid vasculitis manifesting as intra-abdominal hemorrhage. Mayo Clin Proc 1995; 70:565–569. Lebowitz WB. The heart in rheumatoid arthritis (rheumatic disease): a clinical and pathological study of 62 cases. Ann Intern Med 1963; 58:102–123. Weintraub AM, Zvaifler NJ. The occurrence of valvular and myocardial disease in patients with chronic joint deformity. Am J Med 1963;35:145–162. Sokoloff L. Cardiac involvement in rheumatoid arthritis and allied disorders: current concepts. Mod Conc Cardiovasc Dis 1964;33:847–850. Lie JT. Coronary vasculitis. Arch Pathol Lab Med 1987;111:224–233. Lie JT. Systemic, cerebral, and pulmonary segmental mediolytic arteriopathy: villainous masqueraders of vasculitis. Cardiovasc Pathol 1996;5:305–314. Lie JT. Biopsy diagnosis of systemic vasculitis. Baillière Clin Rheumatol 1997;11:219–236.
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Figure 6. Unsuspected fatal pancreatitis in rheumatoid arthritis. Autopsy shows pancreas with acute (A), healing (B), and healed (C) vasculitis. (Hematoxylin-eosin: A 3160; B and C 3400.)
33. Puéchal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis: a clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995;38: 1618–1629. 34. Barker A. Rheumatoid arthritis and rheumatoid heart disease. NZ Med J 1971;73:14–18. 35. Voyles WF, Searles RP, Bankhurst AD. Myocardial infarction caused by rheumatoid vasculitis. Arthritis Rheum 1980;23:860–863. 36. Lie JT. Rheumatoid arthritis and heart disease. Prim Cardiol 1982; 10(10):137–152. 37. Aboumrad MH, Fine G, Horn RC Jr. Intimal hyperplasia of small mesenteric arteries. Arch Pathol Lab Med 1963;75:196–200. 38. McGregor DH, Pierce GE, Thomas JH, Tilzer LL. Obstructive lesions of distal mesenteric arteries. Arch Pathol Lab Med 1980;104:79–83. 39. McCurley TL, Collins RD. Intestinal infarction in rheumatoid arthritis. Arch Pathol Lab Med 1984;108:125–128.
40. Lie JT. Gastrointestinal vasculitis and vasculitis associated with gastrointestinal diseases. Cardiovasc Pathol 1998;7(2):109–118. 41. Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21:883–909. 42. Ramos M, Mandybur TI. Cerebral vasculitis in rheumatoid arthritis. Arch Neurol 1975;32:271–275. 43. Cerventes-Perez P, Toro-Perez AH, Rodriquez-Jurado P. Pulmonary involvement in rheumatoid arthritis. JAMA 1980;243:915–919. 44. Mallory BT. Case records of the Massachusetts General Hospital: cases 22141,22142. N Engl J Med 1936;214:690–698. 45. Clark WS, Kulka P, Bauer W. Rheumatoid arthritis with aortic regurgitation. Am J Med 1957;22:580–592. 46. Zvaifler NJ, Weintraub AM. Aortitis and aortic insufficiency in the chronic rheumatic disorders: a reappraisal. Arthritis Rheum 1963;6: 241–245.
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Figure 7. Intestinal necrotizing vasculitis (A) coexisting with healing vasculitis (B) in resected gangrenous small bowel. (Hematoxylin-eosin: A 3160; B 3400.)
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Figure 8. (A) Granulomatous coronary arteritis with intramural rheumatoid nodules, one of which (boxed area) is shown close-up in (B). (Hematoxylin-eosin: A 340; B 3160.)
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Figure 9. Necrotizing vasculitis of epicardial (A) and intramyocardial (B) coronary arteries in rheumatoid arthritis. (Hematoxylin-eosin: A 340; B 3160.)
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Figure 10. (A) Granulomatous coronary arteritis with intramural rheumatoid nodule (arrows) coexisting with granulomatous myocarditis (B). (Hematoxylin-eosin: A 364; B 3400.)
Figure 11. (A) External view of aneurysmal ascending aorta (AA) with aortic regurgitation in a rheumatoid arthritis patient who died of congestive heart failure. (B) The aorta at autopsy showed granulomatous aortitis with intramural necrobiotic nodules (NN). (Hematoxylin-eosin: B 3160.)
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Figure 12. Rheumatoid aortitis with subendothelial (arrow) intimal (A) and adventitial (B) necrobiotic nodules in different parts of the same aorta. (Hematoxylin-eosin: A and B 3160.)
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Figure 13. Aortic valvulitis in rheumatoid arthritis: (A) one with florid granulomatous infiltrate containing giant cells and (B) another with diffuse lymphocytic infiltrate and necrobiotic nodules (arrows). (Hematoxylin-eosin: A and B 3160.)
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Figure 14. Progressive intimal thickening (double-headed arrows) corresponding with increasingly more intense lymphocytic infiltrates in rheumatoid aortitis is shown in (A), (B), and (C); the granulomatous aortitis is shown in (D). (Hematoxylin-eosin: all 3160.)