Polyarteritis Nodosa

GRAND ROUNDS CLINICIAN’S CORNER AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER

John H. Stone, MD, MPH Polyarteritis nodosa (PAN) is regarded rightly as the grandfather of the vas- CASE PRESENTATION culitides. In this Grand Rounds, the case of a 30-year-old man with a 12- A 30-year-old man was referred for evaluation and treatment of Still dis- year illness is described. The patient presented with daily fevers, tachycar- ease. His illness had begun 12 years dia, and cutaneous ulcers on his distal extremities. He eventually developed earlier when, as a high school senior, mononeuritis multiplex. Because of the striking pattern of his fevers, he was he developed daily temperatures of diagnosed for many years as having adult-onset Still disease. Following the 38.4°C to 38.9°C. Following an exten- addition of daily cyclophosphamide to his long-standing regimen of pred- sive evaluation, he was given the diag- nisone, the patient’s disease entered remission for the first time in more than nosis of Still disease (systemic-onset a decade. He was ultimately able to discontinue all of his immunosuppres- juvenile rheumatoid arthritis) and treated with indomethacin. Indo- sive medications. The case is discussed in the context of the first patient ever methacin helped control the fevers, described with PAN, the classic report of Kussmaul and Maier. which resolved after approximately 1 JAMA. 2002;288:1632-1639 www.jama.com year. However, 3 years later, the fevers returned. He was hospitalized on sev- acetylsalicylic acid (325 mg/d), and skin of his abdomen and flanks and the eral occasions after developing tem- several vitamins and supplements. At medial section of his knees. There was peratures that were as high as 40.0°C age 30, he was taking an average of 28 generalized livedo reticularis over his and responded only to high doses of pills a day. skin (including his face), a large, well- corticosteroids. The patient started a The patient had been married for 3 healed scar from a previous ulcer over prednisone regimen that he continued years at the time of his presentation. He his left medial malleolus, several active for the next 8 years, with frequent and his wife had been attempting to ulcerations on the dorsal surfaces of his attempts to taper his dose on an conceive a child for approximately 12 feet, and significant digital pulp loss in alternate-day basis. Despite the pred- months, without success. The patient several toes of the left foot. Motor nisone, 1 year later the patient began worked as a school librarian and did not strength testing revealed weakness of the to develop purple toes, digital tissue smoke or drink. His family medical his- left foot flexors. loss, and foot ulcers (FIGURE 1A-B). tory was noncontributory. The review Laboratory testing was remarkable Until the onset of his problem at 18 of systems was remarkable for a dif- for a white blood cell count of years of age, the patient was in good fuse, lacy discoloration of the skin. 28700ϫ103/µL, a hematocrit level of health. Since starting prednisone treat- Some months before his evaluation, the 33.7%, and a platelet count of ment, however, he had developed pos- patient had undergone biopsies of his 285000ϫ103/µL. The patient’s serum terior subcapsular cataracts, osteopo- skin, sural nerve, and gastrocnemius creatinine level was 1.0 mg/dL (88 rosis, and mild glucose intolerance. At muscle that revealed vasculitis of µmol/L), and his urinalysis showed 1+ his evaluation, his prednisone dose medium-sized arteries with fibrinoid protein but no cells. The erythrocyte was 40 mg/d alternating with 16 mg/d. necrosis (FIGURE 2). sedimentation rate was 40 mm/h. As- On the days that he took the lower As the patient walked to the examin- steroid dose, he experienced fevers. To ing room, he was observed to have a Author Affiliation: Division of Rheumatology, Johns control the pain from his ulcers, he foot-slapping gait caused by a left foot Hopkins Vasculitis Center, Johns Hopkins University took up to 9 tablets of acetaminophen drop. On examination, he was afebrile School of Medicine, Baltimore, Md. Corresponding Author and Reprints: John H. Stone, with codeine each day. His other and normotensive and had a normal res- MD, MPH, Johns Hopkins Vasculitis Center, 5501 Hop- medications included etodolac (400 piratory rate, but his resting pulse was kins Bayview Circle, JHAAC 1B.23, Baltimore, MD 21224 (e-mail: [email protected]). mg twice daily), pentoxifylline (400 138/min. He had a cushingoid face and Grand Rounds at The Johns Hopkins Hospital Sec- mg 3 times/d), alendronate (10 mg/d), a so-called buffalo hump at the junction Editors: David B. Hellmann, MD, D. William Schlott, MD, Stephen D. Sisson, MD, The Johns Hop- trimethoprim-sulfamethoxazole DS (3 tion of his shoulders and neck. He had kins Hospital, Baltimore, Md; David S. Cooper, MD, times a week), dapsone (25 mg/d), truncal obesity and purple striae over the Contributing Editor, JAMA.

Figure 1. Cutaneous Manifestations of the Patient’s Polyarteritis Nodosa

A B

A, Ulcerations appear on the patient’s right foot; B, digital tissue loss is apparent in several toes of the left foot. say results for antinuclear antibodies within 1 year of presentation.3 In con- Figure 2. Patient’s Skin Biopsy Specimen and anticardiolipin antibodies were trast, our patient had never experi- negative. The result of the Russell vi- enced arthritis at any point in his per venom test was 35.1 seconds (nor- course. The patient also had no lymph- mal: 27.0-45.0 seconds), and a rapid adenopathy, pharyngitis, spleno- plasma reagin test was nonreactive. Re- megaly, or serositis, other features of sults of a serum immunofluorescence the disorder described by Still. Pa- assay for antineutrophil cytoplasmic an- tients with Still disease often present tibodies (ANCA) were negative, as were with a rash: a fine, evanescent, salmon- test results for hepatitis B and C. A chest colored eruption that demonstrates a radiograph revealed no abnormalities. predilection for the proximal limbs and trunk. Our patient’s livedo reticularis Biopsy of the skin from the edge of an ulcer shows DISCUSSION and lower extremity ulcers were dis- leukocytoclasis and fibrinoid necrosis in a medium- Diagnostic Impression sized muscular artery situated at the junction of the tinctly different from the typical Still deep dermis and subcutaneous fat (hematoxylin- Still disease was first described in 1897 disease rash. In short, the patient’s skin eosin, original magnification × 400). by George Still, a London physician who lesions, clinical evidence of a mono- entitled his original treatise “On a Form neuritis (the foot drop), and vasculitis of Chronic Joint Disease in Children.”1 of medium-sized arteries suggested an- ceeded swiftly to death during his 30- Still observed that the disease nearly al- other explanation for the cause of the day hospitalization in Freiburg, Ger- ways began “before the second denti- patient’s illness: polyarteritis nodosa many. Recounting the case, Kussmaul tion,” but an adult form of the condi- (PAN). and Maier wrote that Seufarth was tion was described in 1971.2 Quotidian “[o]ne of these patients for whom one fevers, one of the hallmarks of Still dis- First Case can already give the prognosis before ease, characteristically occur with high In the inaugural volume of the Deut- the diagnosis. The first impression was temperature spikes followed by defer- sches Archiv fu¨r Klinische Medizin (Ger- one of a lost soul whose...days were vescence within hours. Eighty percent of man Archive for Clinical Medicine),4 numbered....”4 patients have temperatures of at least Adolf Kussmaul and Rudolf Maier re- Seufarth, who had felt unwell for at 40°C during these febrile episodes.3 Our ported the case of a 27-year-old jour- least 1 month before presentation, was patient’s fevers, which frequently fit this neyman tailor named Carl Seufarth.4,5 febrile (38.2°C) and tachycardic on ad- pattern, were the principal reason for be- Although they were not the first to remission. Throughout his hospitaliza- lieving that Still disease might be the cor- port a patient with features of PAN,6,7 tion, he experienced intermittent fe- rect diagnosis. However, several other Kussmaul, an internist, and Maier, a pa- vers (as high as 39.2°C), and his pulse features of the patient’s illness sug- thologist, were the first to recognize the ranged from 112 to 140/min. He gested an alternative explanation. constellation of findings as a new clini- “climbed up the two tall flights of stairs Ninety-five percent of patients with cal entity. Seufarth’s illness had begun to the internal medicine clinic with- adult-onset Still disease have arthritis perhaps several months earlier but pro- out assistance...[but] felt so weak that

©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, October 2, 2002—Vol 288, No. 13 1633 POLYARTERITIS NODOSA he immediately had to go to bed.” He ture, there may be no more vivid de- to leave him. Death occurred on June 3rd complained of 1 day of numbness on scription of a rapidly advancing mono- at2o’clock in the morning.” the volar aspect of the thumb and the neuritis multiplex. At autopsy, visible nodules were 2 neighboring fingers of the right hand. With the limited therapeutic arma- present along medium-sized arteries Throughout the ensuing days, this mi- mentarium of his day, Kussmaul could (FIGURE 3A-B): “One glimpse of the nor neurological deficit grew more pro- do little more than wonder about the pa- transected muscles...immediately nounced: “Already in the next days the tient’s inexorable decline. He puzzled demonstrated something unusual. general weakness increased so rapidly over the patient’s condition and docu- Namely...numerous, whitish small that he was unable to leave the bed, mented the clinical deterioration care- tumors up to the size of poppy seeds [and] the feeling of numbness also ap- fully. “OnMay30th...pea-sized nod- and hemp seeds.” The localization of peared in the left hand.” The muscle pa- ules were discovered in the subcutaneous inflammation to the perivascular ralysis progressed quickly but at an in- skin of the abdomen and chest....” sheaths as well as to the media and outer consistent rate. It “accelerated for one Kussmaul excluded 1 common malady layers of the arterial walls, combined or more days, and then on the follow- of the day—trichinosis—because the with the nodular thickening over blood ing days seemed to improve again- subcutaneous nodules were atypical of vessels, led Kussmaul and Maier to sug- . . . but such improvements were not that disease, as were the overt indica- gest the name periarteritis nodosa. stable and soon things were worse than tions of Bright disease (inflammation ever.” The overall effect was devastat- within the kidneys).8 Seufarth’s death was Naming Polyarteritis Nodosa ing: “Before our eyes, a young man de- described poignantly: “On June 2nd, the For decades after the description of this veloped a general paralysis of the vol- patient was in a state of extreme weak- first case of PAN, most forms of vascu- untary muscles....[He] had to be fed ness. He was scarcely able to speak, lay litis were termed periarteritis nodosa. by attendants, and within a few weeks with persistent severe abdominal and Newly recognized types of this disease was robbed of the use of most of his muscle pains, opisthotonically stretched, were characterized and classified ac- muscles.” In the entire medical litera- whimpering, and begged the doctors not cording to features similar to or dis- tinct from those of PAN.9,10 For example, early cases of what became Figure 3. Drawings by Kussmaul and Maier known as Kawasaki disease were la- beled infantile periarteritis nodosa be- A Small Muscular Artery From JejunumB Nodular Thickening of Coronary Arteries cause aneurysms within the coronary arteries in that disease are similar to the lesions of PAN.11,12 In the early 1900s, Ferrari13 and Dickson14 proposed the name polyarteritis nodosa, partly to dis- tinguish the disorder described by Kuss- maul and Maier4 from the vascular lesion of tertiary syphilis. Furthermore, the term polyarteritis nodosa emphasized the panarteritic nature of this disease and underscored the fact that multiple arteries are affected by the process.15

Epidemiology Studies of the epidemiology of PAN have been hampered by the disease’s evolv- ing definition through the decades. Wohlwill16 was the first to detect a vari- ant of PAN in which glomeruli (small blood vessels, ie, differentiated capillaries) were involved prominently. In 1948, Davson et al17 suggested dividing PAN patients into 2 groups according to the presence or absence of glomerulonephritis. One group of patients, Davson and Reprinted with permission from the Mayo Foundation.5 B, The epicardial arteries appear as “thickened ...mis- colleagues noted, demonstrated renal vas- shapened [sic], nodular, whitish-yellow cords.”5 culitis only in medium-sized vessels of

1634 JAMA, October 2, 2002—Vol 288, No. 13 (Reprinted) ©2002 American Medical Association. All rights reserved. POLYARTERITIS NODOSA the kidneys (sparing the glomerulus). We over weeks to months. Many of the ini- tal) nerves first and usually begins now refer to disease such as this group tial symptoms of PAN are recognized asymmetrically. For example, our pa- had as classic PAN. In contrast, patients only in retrospect, once the diagnosis has tient presented with a left foot drop; in the other group had glomerular inflam- been established. Fevers, a common fea- Seufarth’s hand complaints first in- mation with or without medium-sized ture at diagnosis, rarely occur in such volved the right hand and then the left. vessel involvement, a disease subset des- prominent isolation as in our patient. In advanced stages, the neuropathy may ignated microscopic PAN. More recently, The characteristics of fever in PAN vary mimic a confluent, symmetrical poly- microscopic PAN has been renamed from one patient to another, ranging neuropathy, but a careful history tak- microscopic polyangiitis in recognition of from intermittent, low-grade fevers (as ing may unmask its initial asymmetry. its tendency to involve not only arteries Seufarth experienced) to high fevers with Nerve conduction studies detect the but also capillaries and veins.18 The fre- chills (as our patient occasionally expe- typical axonal pattern of nerve injury and quent occurrence of ANCA in patients rienced). Malaise, fatigue, weight loss, identify involved nerves for biopsy. The with microscopic polyangiitis suggests and myalgias are also common in PAN. sural nerve, which mediates sensory per- that this disease differs from classic PAN Arthralgias of large joints (knees, ankles, ception but not motor function, is the not only pathologically but also per- elbows, and wrists) occur in up to 50% one that most commonly undergoes bi- haps etiologically. Because of changes in of patients,24 but true synovitis occurs opsy. Because muscle tissue is highly vas- the definition of PAN, many early stud- in only a minority. cular and may harbor involved vessels ies of this disease’s epidemiology included Vasculitis of medium-sized arteries even in the absence of symptoms or signs patients with microscopic polyangiitis usually produces 1 of 4 cutaneous find- (such as an elevated serum creatine ki- and probably other diseases as well. ings, all of which may occur in the same nase level), biopsies of the gastrocne- The 1994 Chapel Hill Consensus patient: livedo reticularis, nodules, ul- mius muscle should be performed si- Conference18 on the nomenclature of cerations, and digital ischemia.25 Any multaneously.28 Alternatively, biopsies of systemic vasculitides defined classic event leading to disordered blood flow the superficial peroneal nerve and the PAN as necrotizing inflammation of through medium-sized arteries (eg, cold peroneus brevis muscle may be per- medium-sized or small arteries that or vasospasm) can cause a livedoid pat- formed. Advanced mononeuritis multi- spares the smallest blood vessels (ar- tern of skin discoloration. However, the plex can be an enormously disabling terioles, venules, and capillaries) and livedo reticularis caused by active vas- problem from which recuperation is is not associated with glomerulone- culitis does not blanch upon pressure. measured in months or years, if at all. Re- phritis. Under this strict definition, clas- Nodules and ulcers tend to occur on the sidual nerve dysfunction in the form of sic PAN is believed to be rare. From lower extremities, particularly near the muscle weakness or painful neuropa- 1988 to 1994, not a single case of clas- malleoli and in the fleshy parts of the thy is common. The patient’s degree of sic PAN was reported by the Norwich calf. Nodules frequently evolve into ul- recovery is difficult to predict. Health Authority (England), which cerations with scalloped borders. Al- The gastrointestinal manifestations of serves an area with a population of more though nodular lesions are the clini- PAN (FIGURE 4) occur in approxi- than 400000.19 Most other reported an- cal finding from which the name mately half of all patients.27 These symp- nual incidence rates have ranged from periarteritis nodosa was derived, they are toms are among the most challenging to 2 to 9 cases per million annually.20-22 in fact probably the least common cu- diagnose correctly because of their non- PAN appears to affect men and women taneous manifestation of this disease. specific nature and the requirement for with approximately equal frequencies Medium-sized arteries lie within the either mesenteric angiography or surgi- and to occur in all ethnic groups. deep dermis and in the adipose tissue cal exploration. Postprandial abdomi- The highest reported incidence rate of below the skin. Thus, the diagnosis of nal pain (intestinal angina) is common. the disease, 77 cases per million, oc- PAN can be made by skin biopsies of Either mesenteric infarction or aneurys- curred in an area hyperendemic for hepa- nodules or ulcer edges that are suffi- mal rupture in PAN is a disastrous com- titis B virus (HBV) infections.23 With the ciently deep to capture lobules of sub- plication of mesenteric artery involve- availability of the HBV vaccine, the num- cutaneous fat. Digital ischemia, often ment by PAN, with high mortality rates.29 ber of cases associated with this viral in- accompanied by splinter hemor- Angiography of the mesenteric (and re- fection have declined substantially. Hepa- rhages, sometimes leads to tissue loss. nal) vessels (Figure 4B) reveals mul- titis B virus now probably accounts for Mononeuritis multiplex, the infarc- tiple microaneurysms, ranging in size less than 10% of all cases of PAN in the tion of named nerves (eg, the sural, pe- from lesions that are barely visible to developed world (L. Guillevin, oral com- roneal, radial, or ulnar nerves), occurs those large enough to rupture on occa- munication, May 2002). in approximately 60% of patients with sion. Sometimes PAN is detected at cho- PAN.26,27 In vasculitis, mononeuritis lecystectomy or appendectomy in the ab- Clinical Features multiplex results from inflammation in sence of other disease manifestations.30 PAN typically develops subacutely, with the vasa nervorum. Vasculitic neuropa- In such cases, surgical removal of the in- the onset of constitutional symptoms thy tends to involve the longest (ie, dis- volved organ is sometimes curative.

Intraparenchymal renal inflamma- ment is a frequent finding. Congestive The sera of some patients with PAN tion is a major feature of PAN, found heart failure and myocardial infarc- are positive for ANCA when tested by in 40% of patients.27 Because of the dis- tion sometimes result. immunofluorescence (ie, showing ei- ease’s predilection for medium-sized, With less regularity, PAN may in- ther a cytoplasmic or perinuclear pat- muscular arteries, the inflammatory volve a host of other organs, including tern of immunofluorescence, more process targets the renal and interlo- the brain, eyes, pancreas, testicles, ure- commonly perinuclear). However, spe- bar arteries, occasionally involving the ters, breasts, and ovaries. However, for cific enzyme immunoassays for anti- smaller arcuate and interlobular arter- reasons that are not understood, PAN bodies to proteinase-3 or myeloperoxi- ies as well but sparing the glomeruli. spares the lungs. The occurrence of pul- dase (the 2 antigens known to be The primary renal manifestations monary lesions (pulmonary nodules, associated with systemic vasculitis) are of PAN are microaneuryms within cavities, infiltrates, or alveolar hemor- negative in classic PAN.33 Positive en- the kidney, large wedge-shaped renal rhage) in systemic vasculitis shifts the zyme immunoassays for antibodies to infarctions that are visible on cross- differential diagnosis in favor of vas- these specific antigens are much more sectional imaging studies, and mild to culitides commonly associated with consistent with Wegener granuloma- moderate renin-mediated hyperten- ANCA (Wegener granulomatosis, mi- tosis, microscopic polyangiitis, or the sion. Proteinuria and hematuria are croscopic polyangiitis, and the Churg- Churg-Strauss syndrome. common on urinalyses, but red blood Strauss syndrome), antiglomerular cell casts are exceptional because they basement membrane disease (Good- Pathology indicate glomerulonephritis. pasture disease), and other disorders. PAN has a striking tendency to involve Tachycardia is common and often medium-sized muscular arteries. It striking in PAN, as both our patient and Serology spares the aorta and its major branches, Seufarth illustrate. Specific heart le- Assays for antinuclear antibodies and as well as capillaries and small arteri- sions are rarely diagnosed during life, rheumatoid factor are also generally oles that lack muscular coats. In con- but autopsy series indicate cardiac negative in PAN, albeit low nonspe- trast to many other forms of vasculitis, involvement in a majority of pa- cific titers of these antibodies may be PAN also spares the venous system tients.31,32 Seufarth’s epicardial arter- detected. Patients with HBV-associ- (FIGURE 5). Although Kussmaul and ies resembled the pathological appear- ated PAN are generally hypocomple- Maier4 termed the disorder periarteritis ance of arteries at other sites: “The left mentemic, regardless of whether they nodosa, the site of the earliest lesion in anterior descending coronary artery and have demonstrable cryoglobulins. The PAN remains a matter of debate (J. Jen- several branches of the right coronary erythrocyte sedimentation rate and C- nette, oral communication, April 2002) artery...[were] almost entirely thick- reactive protein are often useful in lon- even 150 years after the first unequivo- ened to misshapened [sic], nodular, gitudinal evaluations of disease activ- cal case description.6 Because of the ten- white-yellowish cords” (Figure 3B).5 ity but are nonspecific and do not dency of PAN to involve branch points, Patchy necrosis of the myocardium correlate well with the presence or ab- it is conceivable that the earliest lesion caused by subclinical arteriolar involve- sence of active disease in all patients. occurs in the intima.

Figure 4. Gastrointestinal Manifestations of Polyarteritis Nodosa in 2 Patients

A External Stomach SurfaceB Mesenteric Angiogram

A, Whitish, nodular inflammatory infiltrate tracking the course of medium-sized stomach arteries; B, mesenteric angiogram from a different patient demonstrates dif- fuse involvement of the gastrointestinal tract arteries supplying the small and large bowel. Panel A is courtesy of Grover Hutchins, MD, Department of Pathology, The Johns Hopkins University School of Medicine.

condition. Indeed, they mistook the Figure 5. Jejunal Specimen Obtained at Laparotomy From a Patient Who Died of Complications of Mesenteric Ischemia Related to Polyarteritis Nodosa “countless small nodules” found at autopsy for an undeveloped parasite. Af- ter the publication of an initial report that an infestation of nematodes had caused the disease,37 Kussmaul and Ma- ier later recanted this assertion, likely with some embarrassment. The association of some cases of PAN with HBV infection was first described in 1970.34 PAN develops early in the course of HBV infection, usually within the first 6 months, and is therefore usually the first indication of an HBV infection.38 Serum hepatic transaminase levels may be normal in up to 50% of cases associated with HBV. Seroconversion from hepatitisBean- tigen positivity to the production of anti–hepatitis B e antibodies usually sig- nals recovery. Liver biopsies in HBV- associated cases of PAN show chronic The internal elastic lamina of the artery has been focally disrupted by the inflammatory process (arrows). An area of fibrinoid necrosis is indicated as well (X) (elastin stain, original magnification × 400). The larger vessel, a vein, hepatitis. Numerous other infectious is not involved (note its intact internal elastic lamina). Reprinted with permission from Excerpta Medica Inc.29 agents have been implicated in PAN and other forms of systemic vasculitis (in- Acute lesions swiftly evolve into a pan- Chronic arterial narrowing may result. cluding streptococcal infections in arteritis with degeneration of the arte- Hepatitis B virus–associated PAN childhood PAN),39 but consistent proof rial wall, various amounts of destruc- appears to be an immune complex– of a role for any specific microbial tion of the external and internal elastic mediated disease. The virus’s surface pathogen in causing classic PAN re- lamina, and fibrinoid necrosis. The cel- antigen and antibody complexes are mains absent. lular infiltrate is pleomorphic, with both present in the circulation.34,35 Deposits polymorphonuclear cells and lympho- of HBV surface antigen, immunoglob- Treatment cytes present in various degrees at dif- ulin, and complement are found in For cases of idiopathic PAN, corticoste- ferent stages. Degranulation of neutro- the vasculitic lesions of muscular roids and cytotoxic agents remain the phils within and around the arterial wall arteries, dermal capillaries, glomeruli, cornerstones of treatment.40 Approxi- leads to leukocytoclasis. In time, this and vasa nervorum.34,36 Serum mately half of patients with PAN achieve inflammation leads to transmural necro- complement levels are low during remissions or cures with high doses of sis and a homogeneous, eosinophilic periods of active HBV-associated corticosteroids alone.41 Cyclophospha- appearance to the blood vessel wall (fibri- PAN, consistent with complement mide (eg, 2 mg/kg orally each day, or 0.6 noid necrosis). The vascular wall inflam- consumption by immune complex g/m2 intravenously every month, de- mation in PAN may be strikingly seg- deposition. In contrast to that of PAN creased in the setting of renal dysfunc- mental, affecting only part of the cases associated with HBV, the role of tion) is indicated for patients whose dis- circumference of a given artery (Figure immune complexes in the patho- ease is refractory to corticosteroids or 5). Segmental necrosis, in turn, leads to physiology of idiopathic PAN, if any, who have serious involvement of ma- aneurysm formation. During later stages, remains unclear. jor organs. The Five Factor Score24 has complete occlusion may occur second- been used to delineate which patients ary to endothelial proliferation and Etiology and Immunopathogenesis would benefit from cyclophosphamide thrombosis. Throughout involved tis- The final sentence of the report by Kuss- therapy from the outset of treatment. It sues, the coexistence of acute and healed maul and Maier4 reads: “We would only was developed in a cohort of 336 pa- lesions is typical. Features of granulo- like to add that we looked for syphilis tients with either polyarteritis nodosa or matous vasculitis are absent. Acute PAN in Seufarth during his life and after Churg-Strauss syndrome. Five clinical evolves into a sclerotic process with fibro- death, but without any positive re- features were associated with mortal- sis of the damaged arterial wall and mes- sult.” Thus, the authors of the original ity: gastrointestinal bleeding, perfora- enchymal organization. In some cases, case description strongly suspected an tion, infarction, or pancreatitis; renal in- there is also recanalization of thrombi. infection as the cause of their patient’s sufficiency (serum creatinine level

Ͼ1.58 mg/dL [139.7 µmol/L]); protein- samples before undertaking this ness, the physician must continually re- uria higher than 1 g/d; involvement of therapy. By the time he had made ar- evaluate the diagnostic information the central nervous system; and cardi- rangements for sperm banking and re- available, even while proceeding with omyopathy. Each of these factors car- turned for treatment 2 months later, he what appears to be the appropriate ries an added risk of mortality of ap- had developed several deep skin ulcer- therapy. From complex clinical sce- proximately 10%. Developers of the ations and a new right foot drop. narios, features of a specific disease may score have suggested that patients with At the start of cyclophosphamide emerge in time, permitting more pre- Five Factor Scores of 0 might be treated therapy (2 mg/kg per day), the patient’s cise diagnoses and offering new av- effectively without cyclophosphamide daily prednisone dose was increased to enues for therapy. In this case, the skin but that the presence of any of these 5 40 mg (the alternate-day corticoste- lesions, foot drop, and biopsy-proven factors associated with a poor progno- roid taper was abandoned). Albeit effec- vasculitis of medium-sized muscular ar- sis should lead to the consideration of tive for some forms of inflammation, teries cast the patient’s fever pattern in cyclophosphamide treatment.25 alternate-day corticosteroid regimens a new light and led to the specific di- Treatment of HBV-associated PAN are less effective in vasculitis.42 The agnosis of PAN. with immunosuppressive agents has del- patient also began taking 1 single- Second, many physicians and phy- eterious long-term effects on the liver.41 strength tablet of trimethoprim- sicians-in-training view PAN as an in- Fortunately, the availability of effective sulfamethoxazole daily as prophylaxis variably chronic illness with univer- antiviral agents has revolutionized the against Pneumocystis carinii pneumo- sally toxic treatments. On the contrary, treatment of HBV-associated cases in re- nia. Finally, his complete blood cell this case illustrates that with careful cent years.24 One effective strategy in- count was checked every 2 weeks, with treatment, close follow-up, and the rig- volves the initial use of prednisone (1 the intention of keeping his white blood orous use of measures designed to pre- mg/kg per day) to suppress the inflam- cell count at least 4000ϫ103/µL. vent common complications of treat- mation.24 Patients begin 6-week courses Because of his previously refractory ment (eg, frequent blood cell count of plasma exchange (approximately 3 ex- disease, the prednisone was tapered checks and Pneumocystis carinii pro- changes per week) simultaneously with slowly. By 6 months, he had tapered his phylaxis), patients with PAN may the start of prednisone. The glucocor- daily dose of prednisone from 40 mg achieve excellent outcomes. Former ticoids are tapered off rapidly (total to 15 mg, with healing of his ulcers for recommendations for the use of cyclo- course, approximately 2 weeks), fol- the first time in years. He was able to phosphamide in treating systemic vas- lowed by the initiation of antiviral discontinue all of his pain medica- culitis included the continuation of the therapy (eg, lamivudine at 100 mg/d). tions. Ten months after starting cyclo- medication for 1 full year after the phosphamide treatment, the patient and achievement of disease remission. Al- SCENARIO RESOLUTION his wife celebrated the birth of a daugh- beit effective in inducing disease re- By the time he was evaluated, the pa- ter, conceived through in vitro fertil- missions, such regimens led to pro- tient had had PAN for 12 years. High ization. Shortly thereafter, he tapered longed treatment courses and a host of doses of corticosteroids had con- off prednisone for the first time in a de- drug-induced adverse effects. Cur- tained his disease but failed to put it into cade. Cyclophosphamide was discon- rently, even as investigators seek more remission. Despite long-term therapy tinued after 10 months and replaced specific and less toxic treatments for with corticosteroids, he continued to with azathioprine (2 mg/kg per day) for vasculitis, the use of shorter courses of have fevers and active ulcerations on his 1 year. Now, 8 months after discon- cyclophosphamide may optimize the ef- feet and legs. Moreover, the patient had tinuing azathioprine, he remains in re- fectiveness of this drug while minimiz- experienced substantial drug-related mission despite receiving no treating its potential adverse effects. In this morbidity. His cushingoid habitus and ment. The risk of relapse is believed to case, the careful use of cyclophospha- skin fragility betrayed the long-term use be low, although it may be higher than mide put a disease that had been re- of corticosteroids. At age 30 years, he the rate observed in cases associated fractory for more than 10 years into a was osteoporotic (with bone mineral with HBV (Ͻ10%). medication-free remission. densities in the lumbar spine, Ward tri- angle, and femoral neck Ͼ2 SDs be- CONCLUSIONS REFERENCES low age-matched reference values) and This case contains 2 major lessons for 1. Still G. On a form of chronic joint disease in chil- had already undergone bilateral cata- physicians. First, in general terms, one dren [reprinted in Arch Dis Child. 1941;16:156- 165]. Med Chirurgical Trans. 1897;80:47-58. ract surgery. Clearly, his condition re- should be wary of clinging firmly to a 2. Bywaters E. Still’s disease in the adult. Ann Rheum quired cyclophosphamide. Because of diagnosis (in this case, Still disease) Dis. 1971;30:121-133. 3. Pouchot J, Sampalis J, Beaudet F, et al. Adult Still’s his and his wife’s ongoing efforts to con- based purely on nonspecific features disease: manifestations, disease course, and out- ceive a child and concerns about the such as fever. In the absence of symp- come in 62 patients. Medicine. 1991;70:118-136. 4. Kussmaul A, Maier R. Ueber eine bisher nicht be- possibility of infertility with cyclophos- toms, signs, or other findings that are schriebenen Eigenthumliche arterienerkrankung (peri- phamide use, the patient froze sperm pathognomonic for any particular ill- arteritis nodosa), die mit Morbus Brightii und rapid

1638 JAMA, October 2, 2002—Vol 288, No. 13 (Reprinted) ©2002 American Medical Association. All rights reserved. POLYARTERITIS NODOSA fortschreitender allgemeiner muskellahmung Einher- ture of systemic vasculitides: proposal of an interna- cystites aigues de la periarterite noueuse: huit obser- geht. Dtsch Arch Klin Med. 1866;1:484-518. tional consensus conference. Arthritis Rheum. 1994; vations. Annales Medecine Interne (Paris). 1996;147: 5. Matteson E. Polyarteritis Nodosa: Commemora- 37:187-192. 304. tive Translation of the 130-Year Anniversary of the 19. Watts R, Carruthers D, Scott D. Epidemiology of 31. Holsinger D, Osmundson P, Edwards J. The heart Original Article by Adolf Kussmaul and Rudolf Ma- systemic vasculitis: changing incidence or definition? in periarteritis nodosa. Circulation. 1962;25:610-618. ier. Rochester, Minn: Mayo Foundation; 1996. Semin Arthritis Rheum. 1995;25:28-34. 32. Schrader ML, Hochman JS, Bulkley BH. The heart 6. Von Rokitansky K. Über einige der wichtigsten 20. Scott D, Bacon P, Elliott P, et al. Systemic vascu- in polyarteritis nodosa: a clinicopathologic study. Am Erkrankungen der Arterien: Denkschriften der kaiser- litis in district general hospital 1972-1980: clinical and Heart J. 1985;109:1353-1359. lichen Akademie der Wissenschaften (mathematisch- laboratory features, classification and prognosis of 33. Hoffman G, Specks U. Antineutrophil cytoplasmic naturwissenschaftliche Classe). Vienna, kaiserlich- cases. QJM. 1982;203:292-311. antibodies. Arthritis Rheum. 1998;41:1521-1537. ko¨ niglich Hof- und Staatsdruckerei. 1852;4:1-71. 21. Kurland L, Chuang T, Hunder G. The epidemiol- 34. Gocke D, Hsu K, Morgan C, Bombardieri S, Lock- 7. Matteson E. A history of early investigation of poly- ogy of systemic arteritis. In: Lawrence R, Shulman L, shin M, Christian CL. Association between polyarthri- arteritis nodosa. Arthritis Care Res. 1999;12:294-302. eds. The Epidemiology of the Rheumatic Diseases.New tis and Australia antigen. Lancet. 1970;2:1149- 8. Cameron J. Medical eponyms updated: Bright’s dis- York, NY: Gower; 1984:196-205. 1153. ease. Br J Clin Pract. 1991;45:50-52. 22. Sack M, Cassidy J, Bole C. Prognostic factors in 35. Fye KH, Becker MJ, Theofilopoulos AN, Mout- 9. Klinger H. Grenzformen der Periarteritis nodosa. polyarteritis. J Rheumatol. 1975;2:411-420. sopoulos H, Feldman JL, Talal N. Immune complexes Frankfurter Zeitschrift Pathol. 1931;42:455-480. 23. McMahon B, Heyward W, Templin D, et al. Hepa- in hepatitis B antigen-associated periarteritis nodosa: 10. Churg J, Strauss L. Allergic granulomatosis, aller- titis B-associated polyarteritis nodosa in Alaskan Es- detection by antibody independent cell-mediated cy- gic angiitis, and periarteritis nodosa. Am J Pathol. 1951; kimos: clinical and epidemiologic features and long- totoxicity and the Raji cell assay. Am J Med. 1977; 27:277-301. term follow-up. Hepatology. 1989;9:97-101. 62:783-791. 11. Tanaka N, Sekimoto K, Naoe S. Kawasaki dis- 24. Guillevin L, Lhote F, Gayraud M, et al. Prognos- 36. Tsukada N, Koh C, Owa M, Yanagisawa N. Chronic ease: relationship with infantile periarteritis nodosa. tic factors in polyarteritis nodosa and Churg-Strauss neuropathy associated with immune complexes of hepa- Arch Pathol Lab Med. 1976;100:81-86. syndrome: a prospective study in 342 patients. Medi- titis B virus. J Neurol Sci. 1983;61:193-211. 12. Landing BH, Lawson EJ. Are infantile periarteritis cine. 1996;75:17-28. 37. Kussmaul A, Maier R. Aneurysma verminosum nodosa with coronary artery involvement and fatal mu- 25. Stone J, Nousari H. “Essential” cutaneous vas- hominis: verlaufige Nachricht. Dtsch Arch Klin Med. cocutaneous lymph node syndrome the same? com- culitis: what every rheumatologist should know about 1866;1:125-126. parison of 20 patients from North America with pa- vasculitis of the skin. Curr Opin Rheumatol. 2001;13: 38. Guillevin L, Lhote F, Cohen P, et al. Polyarteritis tients from Hawaii and Japan. Pediatrics. 1977;59: 23-34. nodosa related to hepatitis B virus: a prospective study 651-652. 26. Griffin J. Vasculitis neuropathies. Rheum Dis Clin with long-term observation of 41 patients. Medi- 13. Ferrari E. Ueber Polyarteritis acuta nodosa (soge- North Am. 2001;27:751-760. cine. 1995;74:238-253. nannte Periarteritis nodosa), und ihre Beziehungen zur 27. Guillevin L. Polyarteritis nodosa and microscopic 39. Mandell B, Calabrese L. Infections and systemic Polymyositis und Polyneuritis acuta. Beitr Pathol Anat. polyangiitis. In: Ball GV, Bridges SL Jr, eds. Vasculitis. vasculitis. Curr Opin Rheumatol. 1998;10:51-57. 1903;34:350-386. Oxford, England: Oxford University Press; 2002:300- 40. Guillevin L, Lhote F. Treatment of polyarteritis no- 14. Dickson W. Polyarteritis acuta nodosa and peri- 320. dosa and microscopic polyangiitis. Arthritis Rheum. arteritis nodosa. J Pathol Bacteriol. 1908;12:31-57. 28. Said G, Lacroix-Ciaudo C, Fujimura H, Blas C, Faux 1998;41:2100-2105. 15. Arkin A. A clinical and pathological study of peri- N. The peripheral neuropathy of necrotizing arteritis: 41. Lam KC, Lai CL, Trepo C, Wu PC. Deleterious ef- arteritis nodosa. Am J Pathol. 1930;6:401-431. a clinical pathologic study. Ann Neurol. 1988;23:461- fects of prednisolone in hepatitis B surface antigen- 16. Wohlwill F. Ueber die nur Mikroskopisch erken- 465. positive chronic active hepatitis. N Engl J Med. 1981; barre Form der Periarteritis nodosa. Arch Pathol Anat. 29. Levine SM, Hellmann DB, Stone JH. Gastrointes- 304:380-386. 1923;246:377-411. tinal involvement in polyarteritis nodosa (1986- 42. Hunder GG, Sheps SG, Allen GL, Joyce JN. Daily 17. Davson J, Ball J, Platt R. The kidney in periarteri- 2000): presentation and outcomes in 24 patients. Am and alternate-day corticosteroid regimens in treat- tis nodosa. QJM. 1948;17:175-192. J Med. 2002;112:386-391. ment of giant cell arteritis: comparison in a prospec- 18. Jennette J, Falk R, Andrassy K, et al. Nomencla- 30. Blidi M, Quang T, Cassan P, Guillevin L. Chole- tive study. Ann Intern Med. 1975;82:613-618.

The man who discovers a new scientific truth has previously had to smash to atoms almost everything he had learnt, and arrives at the new truth with hands bloodstained from the slaughter of a thousand plati- tudes. —Jose´ Ortega y Gasset (1883-1955)