Attempting to understand polyarteritis nodosa: Have you ever tried?
When, in May, 1997, I came to the Institute for Dermatopathology at Jefferson Medical College and chose polyarteritis nodosa as the subject I would pursue in depth, I could not imagine then that one year later I would be ready for a psychiatrist’s couch. After having read about polyarteritis nodosa in standard textbooks of pathology, dermatology, and dermatopathology, it became apparent to me that the subject was opaque and the nature of “polyarteritis nodosa,” as it was conceived of by Kussmaul and Maier* in 1866, would never be known with surety. It was those co-authors who, more than 130 years ago, recorded the findings in a single patient with what they called periarteritis nodosa. The most important observations of Kussmaul and Maier, in their own words, were thus:
*Kussmaul A, Maier R. über eine bisher nicht beschriebene eigenthümliche Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Deutsches Arch f klin Med 1865-66, I, 484-518.
Observations of Kussmaul and Maier
“There is a generalized and progressive paralyzing of striated muscle, starting with intense muscle pain associated with nephritis, fever . . . diffuse necrotizing enteritis, hemorrhagic erosions of the stomach, diffuse nephritis and bronchitis . . . extensive granular degeneration of the striated muscle including that of the heart, waxy degeneration of individual nerve tubes, cerebral atrophy, and edema of the pia matter. . . . [There is] peculiar, mostly nodal thickening of multiple arteries of the size of a liver artery and smaller than it, with involvement also of coronary arteries. The middle layer of affected arteries are mostly of the muscular type. There is no involvement of capillaries or veins. Most affected arteries are found in the gastrointestinal tract, kidneys, spleen, heart, and striated muscle; involvement is less in arteries of the liver, subcutis, lungs, and phrenic.” The findings by conventional microscopy were as follows. “This peculiar disease of arteries began in the outer sheath of the vessel. . . . The intima of the nodules in arteries is almost intact. Media and adventitia of the nodules show the most relevant changes and active process. The early stages reveal a proliferation of nuclei of the tunica media and externa concurrently. Shortly after that production of cells follows. The cells of fascicles of muscle layers become larger and broader; some cells of fascicles show large nuclei, other several small nuclei; at last free nuclei are found in between the muscle cells. The swelling of the adventitia is more pronounced. It seems like loose tissue. Roundish and spindle-like bodies, often with many nuclei, come into being. In other sites fibrous tissue is formed and surrounds the vessel. This alteration is visible to the eye. Sometimes the changes of the adventitia attack the adjacent parenchymatous parts, and this can be observed best in striated muscle. These alterations of media and adventitia of arteries and their adjacent tissue seem to be the earliest changes of this degeneration. A thickening of the vessel is observed, no luminal alteration is seen, the intima is preserved, and the consistency is not so hard. As the process progresses, the nodules become very hard and show some shrinkage, and then the lumina and intima of arteries also show changes. A so-called regressive metamorphosis can be observed in old nodules. The cells of fascicles of muscularis show fine granular detritus, filled often with granular fat.”
I read and re-read the original article, translated from German,** but could not fathom the meaning of it. No matter how hard I tried, I was unable to gain a sure sense for the disease as it was characterized by Kussmaul and Maier, and communicated to readers by them. That being the case, I decided to devour the English language literature since 1866 about polyarteritis nodosa in an effort to obtain answers to fundamental questions. What follows are some of my queries and answers to them culled from various authors:
**The translation was by Bruno Parades, a former fellow at the Institute who is now a resident in dermatology at the University of Basel in Switzerland.
What kind of vessel(s) are affected in polyarteritis nodosa?
1912: “The most marked changes were in the walls of small arteries, of the size of the branches of the coronary artery of the heart. The larger arteries were not affected.” Beattle JM, Douglas M. A case of polyarteritis acuta nodosa. J Pathol and Bacteriol 1912-13, xvii, 195-8.
1923: “Periarteritis nodosa is an acute inflammatory disease of the smaller arteries . . .” Ophüls W. Periarteritis acuta nodosa. Arch Intern Med 1923; 32:870-98.
1939: “Many of the smaller vessels and capillaries, however, in the lower portion of the cutis as well as in the subcutaneous fat . . . showed inflammatory changes in or around the walls. We were not able to determine in all cases whether these changes affected veins or small arteries but were under the impression that both were involved, the veins, however, less frequently.” Ketron LW, Bernstein JC. Cutaneous manifestations of periarteritis nodosa. Arch Dermatol and Syphil 1939;40:929.
1948: “These early stages consisted of fragmentation, degeneration . . . at the bifurcation of arteries of muscular type near the site of their entrance into viscera . . . veins were involved occasionally in cases with extensive lesions in arteries, but only by direct extension of the inflammation from an adjacent artery.” Zeek PM, Smith CC, Weeter JC. Studies on periarteritis nodosa. III. Differentiation between vascular lesions of periarteritis nodosa and of hypersensitivity. Am J Pathol 1948;24:889-917.
1954: “In and around arterioles in the corium there is an intense inflammatory reaction. Lyell A, Church R. The cutaneous manifestations of polyarteritis nodosa. Br J Dermatol 1954;66:335.
1978: “Classic polyarteritis nodosa, as it was originally described and later categorized, is a necrotizing vasculitis of small- and medium-sized muscular arteries . . . with predilection for bifurcations and branchings of arteries, with distal spread involving arterioles and, in some cases, circumferentially involving adjacent veins.” Fauci AS, Haynes BF, Katz P. The spectrum of vasculitis. Clinical, pathologic, immunologic, and therapeutic considerations. Ann Intern Med 1978;89(Part 1):660-76.
1980: “Polyarteritis is defined . . . pathologically by the presence of a necrotizing inflammation of small and medium-sized arteries.” Cohen RD, Conn DL, Ilstrup DM. Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 1980;55:146-55.
1993: “Cutaneous lesions occur . . . with small-vessel type (palpable purpura) lesions being the most common manifestation. . . . The more diagnostic cutaneous lesions of which suggest larger vessel (e.g., muscular artery) involvement on clinical examination are large “punctate” cutaneous ulcers . . .” Jorizzo JL. Classification of vasculitis. J Invest Dermatol 1993; 100(1)(Suppl).
1994: [The basic process is] “necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.” Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37(2):187-92.
1995: “The classic polyarteritis nodosa (PAN) is a primary (idiopathic) systemic necrotizing vasculitis of small and medium-sized arteries, very rarely veins, and never the large elastic arteries.” Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21(4).
1997: “The characteristic lesion of classic PAN is a panarteritis nodosa involving medium-sized and small arteries.” Barnhill RL, Busam KJ. Ch. 8: Vascular diseases. In: Lever’s Histopathology of the skin. 8th ed. Philadelphia: Lippincott-Raven, 1997:191-2.
What are the histopathologic findings in polyarteritis nodosa and, in particular, where in the vessels does the process begin?
1923: “. . . it probably starts in the adventitia but soon involves all coats of the arterial wall . . .” Ophüls W. Periarteritis acuta nodosa. Arch Intern Med 1923; 32:870-98.
1930: “The beginning stage is characterized by alterative-degenerative changes in the media . . .” Arkin A. A clinical and pathological study of periarteritis nodosa. Am J Pathol 1930;6:401-26.
1939: “. . . in this case the primary lesion occurred in the intima and progressed outward through the wall to the adventitia.” Weir DR. Polyarteritis nodosa. Report of case. Am J Pathol 1939; XV:79.
1953: “The process spreads through the wall of the vessel, the intima usually being the last coat affected.” Zeek PM. Periarteritis nodosa and other forms of necrotizing agents. N Engl J Med 1953;248(18).
1964: “In the initial stage, edema and exudate are seen in the intima with swelling and separation of the adjacent muscle cells.” Alarcón-Segovia D, Brown AL Jr. Classification and etiologic aspects do necrotizing angiitides: an analytic approach to a confused subject with a critical review of the evidence for hypersensitivity in polyarteritis nodosa. Mayo Clin Proc 1964:39(3):205.
1979: “The acute lesions are characterized by fibrinoid necrosis which may affect only the intima but often extends to involve the full thickness of the arterial wall . . .” Kumar V. Ch. 8: Diseases of immunity. In: Robbins SL, Cotran RS (eds). Pathologic basis of disease. 2nd ed. Philadelphia: WB Saunders, 1979:312.
1987: “A focus of necrosis in the arterial wall progresses to involve all portions of the vessel.” Bondi EE, Lazarus GS. Ch. 99. Panniculitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF (eds). Dermatology in general medicine. 3rd ed. New York: McGraw Hill, 1987:1145.
1992: “Early lesions show necrosis of the arterial wall with deposited fibrinoid material and destruction of the elastic lamina . . .” Soter NA. Ch. 48. Necrotizing vasculitis. In: Moshella and Hurley. Dermatology. 3rd ed. Vol. 1, 1992:1191.
What cells make up the infiltrate in polyarteritis nodosa?
1923: “. . . heavy infiltration of the peripheral layer of the adventitia with leukocytes, mostly eosinophils, but there were also a few lymphocytes and plasma cells . . .” Ophüls W. Periarteritis acuta nodosa. Arch Intern Med 1923; 32:870-98.
1930: “. . . a great infiltration of the media and adventitia with polymorphonuclear neutrophils, sometimes also eosinophils, lymphocytes, and plasma cells . . .” Arkin A. A clinical and pathological study of periarteritis nodosa. Am J Pathol 1930;6:401-26.
1934: “. . . another feature not seen in previous sections is the presence of numerous giant cells around the vessels . . .” Haining RB, Kimbal TS. Polyarteritis nodosa. Am J Pathol 1934;10:349-60.
1958: “. . . in the same section proliferative changes of the vessel wall can also be seen, with fibroblasts and multinuclear giant cells . . .” Ruiter M. The so-called cutaneous type of polyarteritis nodosa. Br J Dermatol 1958;70:102-6.
1977: “Neutrophil polymorphs, lymphocytes, plasma cells, and macrophages are present in varying proportions, and often eosinophils are conspicuous.” Crawford T. Ch. 21: Blood and lymphatic vessels. In: Anderson WAD, Kissane JM (eds). Pathology. St. Louis: CV Mosby, 1977:900-1.
1982: “The ulcerated mucosal areas were associated with an acute and chronic inflammatory response and many plasma cells were present. A few multinucleated giant cells were present . . .” Meyer GW, Lichtenstein J. Isolated polyarteritis nodosa affecting the cecum. Dig Dis Sci 1982;27(5):467-9.
1990: “Criteria for the classification of polyarteritis nodosa were developed . . . 10 criteria were selected . . . [one was] presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy.” Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 Criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33(8).
1995: “Contrary to popular belief, the predominant cells in the inflammatory infiltrate of polyarteritis nodosa are not granulocytes, rather, they are macrophages and CD4-positive T lymphocytes . . .” Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21(4).
1997: “. . . An infiltrate present within and around the arterial wall is composed largely of neutrophils showing evidence of leukocytoclasis, although it often contains eosinophils . . . the infiltrate may also contain a significant number of lymphocytes, histiocytes, and some plasma cells . . .” Barnhill RL, Busam KJ. Ch. 8: Vascular diseases. In: Lever’s Histopathology of the skin. 8th ed. Philadelphia: Lippincott-Raven, 1997:191-2.
Atlas of photomicrographs of changes in blood vessels alleged to be those of pan
No criteria are provided for diagnosis of PAN in a single legend presented here. Furthermore, the changes pictured do not seem to represent a single pathologic process. In short, a student of the subject is left baffled by illustrations such as these.
Ophuls W. Periarteritis acuta nodosa. Arch Intern Med 1923; 32:874. Reprinted with permission by the American Medical Association.
Arkin A. A clinical and pathological study of periarteritis nodosa. Am J Pathol 1930;VI:426. Reprinted with permission by the American Society for Investigative Pathology.
Arkin A. A clinical and pathological study of periarteritis nodosa. Am J Pathol 1930;VI:426. Reprinted with permission by the American Society for Investigative Pathology.
Haining RB, Kimball TS. Polyarteritis nodosa. Am J Pathol 1934;X:360. Reprinted with permission by the American Societey for Investigative Pathology.
Zeek PM, Smith CC, Weeter JC. Studies on periarteritis nodosa. Am J Pathol 1948;XXIV:905. Reprinted with permission by the American Society for Investigative Pathology.
Zeek PM, Smith CC, Weeter JC. Studies on periarteritis nodosa. Am J Pathol 1948;XXIV:907. Reprinted with permission by the American Society for Investigative Pathology.
Ruiter M. The so-called cutaneous type of polyarteritis nodosa. Br J Dermatol 1958;70:105. Reprinted with permission by the British Association of Dermatologists.
Borrie P. Cutaneous polyarteritis nodosa. Br J Dermatol 1972; 87:93. Reprinted with permission by the British Association of Dermatologists.
Minkowitz G, Smoller BR, McNutt N. Benign cutaneous polyarteritis nodosa. Arch Dermatol 1991;127(9):1521. Reprinted with permission by the American Medical Association.
Is polyarteritis nodosa fundamentally an expression of leukocytoclastic vasculitis?
1948: “Periarteritis nodosa can be differentiated from hypersensitivity angiitis by (1) the morphologic characteristics of early pre-exudative lesions, (2) the distribution of the lesions in relation to the bifurcation of vessels, (3) the size and type of vessels primarily affected, and (4) by the presence or absence of lesions in the splenic follicular arterioles and in the arteries of the pulmonary circulation.” Zeek PM, Smith CC, Weeter JC. Studies on periarteritis nodosa. III. Differentiation between vascular lesions of periarteritis nodosa and of hypersensitivity. Am J Pathol 1948;24:889-917.
1977: “. . . a patient with systemic vasculitis had the palpable purpuric lower extremity lesions of leukocytoclastic vasculitis and the renal aneurysms of polyarteritis nodosa . . .” deShazo RD, Levinson AI, Lawless OJ, et al. Systemic vasculitis with coexistent large and small vessel involvement – a classification dilemma. JAMA 1977;238(18).
1980: “This disorder [hypersensitivity vasculitis], which was described pathologically by Zeek and associates in 1948, is from a practical standpoint difficult to distinguish from polyarteritis both clinically and pathologically.” Cohen RD, Conn DL, Ilstrup DM. Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 1980;55:146-55.
1990: “. . . some cases labeled CPN [cutaneous polyarteritis nodosa] in the past were what now would be classified as leukocytoclastic vasculitis . . .” Moreland LW, Ball GV. Cutaneous polyarteritis nodosa. Am J Med 1990;88:426-30.
1992: See Table 1.
Table 1. Comparative Features of Vasculitic Diseases
|Vasculitic Syndrome||Vessels Involved||Pathologic Features|
|Polyarteritis nodosa||Small and medium arteries||Necrotizing leukocytoclastic vasculitis|
|Hypersensitivity vasculitis||Postcapillary venules||Necrotizing leukocytoclastic vasculitis|
|Homas PB, David-Bajar KM, Fitzpatrick JE, et al. Microscopic polyarteritis. Report of a case with cutaneous involvement and antimyeloperoxidase antibodies. Arch Dermatol 1992;128.|
1997: “The most common histological finding in our patients was periarteritis of small to medium sized arterioles at the dermal-pannicular junction . . . Necrotizing leucocytoclastic vasculitis of capillaries in the superficial dermis was present in a few cases.” Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol 1997;136:706-13.
Is “microscopic polyarteritis nodosa” really polyarteritis nodosa?
1930: “I wish to call attention to the fact that there is a microscopic form of periarteritis nodosa which can be recognized only by a careful study of tissues, especially with elastica stains of the blood vessels.” Arkin A. A clinical and pathological study of periarteritis nodosa; a report of five cases, one histologically healed. Am J Pathol 1930;6:401-26.
1948: “Fourteen cases of periarteritis nodosa have been described, and divided according to their renal lesions into two main groups . . . The cases in group A are thus all examples of the microscopic form of periarteritis nodosa in which severe renal damage has been present, the diagnosis having been made in most cases only after histological examination.” Davson J, Ball J, Platt R. The kidney in periarteritis nodosa. QJM 1948, New Series, No. 67:175.
1964: “. . . and some differences have been noticed between the lesions associated with drug reactions and classic PAN. Since only small arteries were involved in the drug reaction, the condition has been referred to sometimes as ‘microscopic polyarteritis nodosa.'” Alarcón-Segovia D, Brown AL Jr. Classification and etiologic aspects do necrotizing angiitides: an analytic approach to a confused subject with a critical review of the evidence for hypersensitivity in polyarteritis nodosa. Mayo Clin Proc 1964:39(3):205.
1985: “Microscopic polyarteritis is part of a spectrum of systemic vasculitis, sharing features with both polyarteritis nodosa and Wegener’s granulomatosis.” Savage COS, Winearls CG, Evans DJ, et al. Microscopic polyarteritis: presentation, pathology, and prognosis. QJM 1985;56 (220):467-83.
1992: “The term ‘microscopic polyarteritis nodosa’ is confusing because in renal histopathology a ‘microscopic form’ of PAN has also been described. In contrast to classic PAN where the renal manifestations are seen in the arteries of arcuate size or larger, the renal blood vessels involved in ‘microscopic PAN’ are the smaller interlobular arteries, arterioles, venules, and capillaries.” Homas PB, David-Bajar KM, Fitzpatrick JE, et al. Microscopic polyarteritis. Report of a case with cutaneous involvement and antimyeloperoxidase antibodies. Arch Dermatol 1992;128.
1994: “The name ‘microscopic polyangiitis,’ or alternatively ‘microscopic polyarteritis, connotes pauci-immune (i.e., few or no immune deposits) necrotizing vasculitis affecting small vessels, with or without involvement of medium-sized arteries.” Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international conference. Arthritis Rheum 1994;37(2):187-92.
1995: “The classic polyarteritis nodosa (PAN) is a primary (idiopathic) systemic necrotizing vasculitis of small and medium-sized arteries . . . Involvement of arterioles and the microcirculation, such as the renal glomeruli, are traditionally considered a distinct clinical entity, designated as microscopic polyarteritis (MPA). Because MPA may be associated with circulating antineutrophil cytoplasmic antibodies (ANCA) and because it occurs in the lungs as capillaritis, resembling Wegener’s granulomatosis, it has become fashionable to refer to MPA as microscopic polyangiitis.” Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21(4).
1997: “Unlike WG [Wegener's granulomatosis], uniform criteria for diagnosing MPA [microscopic polyarteritis nodosa] do not exist. Nowadays, the term MPA is best used to describe a patient with evidence of a nongranulomatous small vessel vasculitis associated with a rapidly progressive glomerulonephritis clinically and a focal segmental necrotizing glomerulonephritis pathologically.” Mercado U. Classification of periarteritis nodosa and microscopic periarteritis: comment on the article by Watts et al. Arthritis Rheum 1997;40(4):788-92.
1998: “At present pathologists continue to distinguish classic and microscopic polyarteritis, although the rationale for this separation has been challenged by an increasing number of cases with ‘overlapping syndrome of vasculitis.'” Busan KJ, Barksdale SR, Barnhill RL. Ch. 9: Vasculitis and related disorders. In: Barnhill RL (ed). Textbook of dermatopathology. New York: McGraw-Hill, 1998:191.
Is there a pure cutaneous form of polyarteritis nodosa separate from systemic polyarteritis nodosa?
1954: “We have presented three cases each confirmed by examination of an excised subcutaneous nodule and conclude that there were two forms of polyarteritis nodosa. The first is cutaneous and is characterized by livedo reticularis, ulceration, muscle pains and oedema, and the second visceral in which the skin is involved inconstantly and incidentally during the course of the disease by exanthemata, ecchymoses or gangrene. Subcutaneous nodule are common to both forms.” Lyell A, Church R. The cutaneous manifestations of polyarteritis nodosa. Br J Dermatol 1954;66:335.
1964: “Except for the duration of the disease, it appears to us that one cannot clearly distinguish between a visceral and cutaneous type of periarteritis nodosa . . . these dermatologic changes seen in combination with systemic symptoms are similar in every respect to the cutaneous changes observed in cases of periarteritis nodosa with less prominent systemic symptoms.” Fisher I, Orkin M. Cutaneous form of periarteritis nodosa – an entity? Arch Dermatol 1964;89:180-9.
1972: “It is concluded that 10% of all cases of polyarteritis nodosa, and 30% of those proven histologically, are of this benign [cutaneous] type and that this variety can be easily recognized clinically.” Borrie P. Cutaneous polyarteritis nodosa. Br J Dermatol 1972; 87:87-95.
1974: “Cutaneous periarteritis nodosa is definite vascular disease of the skin with a benign course and a good response to treatment. There is no reason to confuse it with other vascular diseases of the skin or with systemic periarteritis nodosa . . . We do not intend to imply that cutaneous periarteritis nodosa and systemic periarteritis nodosa are different diseases; by all histologic and laboratory criteria, the two syndromes are the same process.” Diaz-Perez JL, Winkelmann RK. Cutaneous periarteritis nodosa. Arch Dermatol 1974;110:407.
1984: “CPN [cutaneous polyarteritis nodosa] is not strictly a cutaneous disorder, however. Systemic symptoms such as fever, arthralgia, neuropathy, and muscle involvement have been documented in large proportions of patient groups.” Mekori YA, Awai LE, Wiedel JD, et al. Cutaneous polyarteritis nodosa associated with rapidly progressive arthritis. Arthritis Rheum 1984;27(5).
1991: “We conclude that benign cutaneous polyarteritis nodosa is not necessarily benign and is closely related to systemic polyarteritis nodosa.” Minkowitz G, Smoller BR, McNutt N. Benign cutaneous polyarteritis nodosa. Relationship to systemic polyarteritis nodosa and to hepatitis B infection Arch Dermatol 1991;127:1520-3.
1998: “It is still an unresolved issue whether a form of PAN exists that is limited to the skin.” Busan KJ, Barksdale SR, Barnhill RL. Ch. 9: Vasculitis and related disorders. In: Barnhill RL (ed). Textbook of dermatopathology. New York: McGraw-Hill, 1998:191.
After having read all of these articles about polyarteritis nodosa, and many more, I came to realize how futile it is to try to understand diseases such as polyarteritis nodosa, allergic granulomatosis of Churg and Strauss, and Wegener’s granulomatosis, the original description of which is murky. My quest for comprehension of the subject of polyarteritis nodosa was not aided by scrutinizing photomicrographs published in articles and chapters. They only made matters worse. Most of them are of poor quality, were “shot” only at high magnification, and do not lend themselves to instructive interpretation.
So here I am about to return to Brasil after one year of attempting vainly to come to grips with the nature of polyarteritis nodosa. If you think that that task is accomplishable, I invite you to try!
This work was done during a Visiting Fellowship at the Institute. Dr. Mesquita is now an assistant professor at Evangélica Medical College of Paraná and pathologist at Patologistas Associados S/C Ltda Laboratory (Santa Casa de Misericórdia de Curitiba Hospital) in Brazil. Reviewed by A. Bernard Ackerman, M.D. and Kenneth S. Resnik, M.D.