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Polyarteritis Nodosa

Travis Howard, MD, Kinza Ahmad, BS, Jerome (Allen) A. Swanson, MD, andSanjay Misra, MD

516/14/$ - seex.doi.org/10.1

ent of Radios reprint requeartment of R93; fax: þ503

The first description of polyarteritis nodosa (PAN) was in 1852 by Karl Rokitansky, apathologist at the University of Vienna. The initial report describes a 23-year-old manwho had a 5-day history of fever and diarrhea. Since then, the definition of PAN hasevolved. The currently accepted definition of PAN comes from the 2012 Chapel HillConference, which classified PAN as a necrotizing arteritis not associated withantineutrophil cytoplasmic antibodies of medium or small arteries without glomerulo-nephritis or vasculitis in arterioles, capillaries, or venules.Tech Vasc Interventional Rad 17:247-251 C 2014 The Authors. Published by Elsevier Inc.All rights reserved.

KEYWORDS Polyaarteritis, nodosa, imaging technique, treatment

The requirement for negative results for antineutro-phil cytoplasmic antibody (ANCA) serology test in

polyarteritis nodosa (PAN) is a useful new change thatallows for discrimination between PAN and ANCA-associated vasculitides, which otherwise have similarpresentations pathologically and clinically. PAN cansolely involve a single organ or present systemically.1 Itmay affect any organ, but for unknown reasons it sparesthe pulmonary and glomerular arteries. PAN can beidiopathic, or it can be associated with an infectiousetiology such as hepatitis B virus (HBV). PAN has beenassociated with various infectious viruses including HBVand human immunodeficiency virus, and the prevalenceof infection-associated PAN is related to the prevalence ofthe infections themselves.2 For example, with the devel-opment of a vaccine for HBV vaccine, the percentage ofpatients with PAN who have HBV have decreased from36% to less than 5%.3,4

In European countries, the incidence of PAN rangesfrom 0-1.6 cases per million and the prevalence is about 31cases per million.5 The mean age of patients at diagnosis is51 years, and men are more frequently involved althoughpeople of any age, sex, and ethnicity can be affected.5

Angiography remains the gold standard for imagingdiagnosis.

front matter & 2014 The Authors. Published by Elsevier053/j.tvir.2014.11.005

logy, Mayo Clinic, Rochester, MN.sts to Sanjay Misra, MD, FSIR, FAHA, Mayo Clinic,adiology, Rochester, MN 55905. Tel.: þ507 293494 4324. E-mail: misra.sanjay@mayo.edu

Clinical Evaluation of thePatient—Physical Examination,History, Laboratory Tests, andTreatmentThe typical presentation of PAN involves the skin orperipheral nerves.5 The skin can be involved and exhibita range of lesions including purpura, livedoid, subcuta-neous nodules, and necrotic ulcers. The main neurologicmanifestation is mononeuritis multiplex, which canpresent with wrist or foot drop etc. Subacute presentationconsists of vague symptoms including fever, weight loss,malaise, headache, and myalgia. The spectrum of diseaseranges from involving a single organ to polyvisceral failure.Patients with involvement of the kidneys typically

present with hypertension, renal insufficiency, or renalfailure. Renal hemorrhage may also present with sponta-neous subcapsular and perirenal hemorrhage. With acuterenal hemorrhage, patients may represent with Wunder-lich syndrome: acute flank pain, flank mass, and hypo-volemic shock.6 Gastrointestinal (GI) symptoms consist ofischemia, infarction, abdominal pain, weight loss, bowelperforation, hemorrhage, pancreatitis, appendicitis, andcholecystitis. The brain, eyes, pancreas, lungs, testicles,ureters, breasts, and ovaries are rarely involved. Five-yearsurvival rate for untreated PAN is 13%.7,8 The outcome ofPAN has improved in patients receiving treatment; 5-yearsurvival rate is approximately 80%.9 The survival rates forpatients with HBV-associated PAN is lower than forpatients with non–HBV-associated disease. With fulminantor polyvisceral disease 5-year survival rate is less than 15%.

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Figure 1 A 27-year-old man who presented with headache,hypertension, and renal insufficiency. A left renal arteryangiogram demonstrates multiple small aneurysms (redarrows) with segmental or subsegmental irregular narrowing(yellow arrows).

Figure 2 A 54 year-old woman with nonhealing ulcerations on herlegs and distal gangrene. A left renal artery angiogram demon-strates small aneurysms (red arrows).

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Relapse occurs in 40% of patients with a median survivalrate of 33 months. Overall, 50% of patients with abdomi-nal involvement develop acute surgical abdomen with amortality rate of 12.5%.The French Vasculitis Study Group has established a

large, well-characterized longitudinal cohort of patientswith PAN and reported a comprehensive series of studieson the natural history and treatment of this disorder. In1996, using regression analytical techniques, this groupderived the “five-factor score” (FFS) as a simple prognostictool for clinicians to use when evaluating patients withvarious forms of vasculitis, including PAN.10,11 The FFSwas revised in 2011 based upon additional data and forPAN now only includes 4 factors associated with increasedmortality: (1) older than 65 years, (2) cardiac symptoms,(3) GI involvement, and (4) renal insufficiency (plasmacreatinine41.7 mg/dL [150 μM/L]). The original FFS hadincluded central nervous system disease (dropped fromthe score in 2011) but did not include age (included in2011). The FFS has been used to stratify patients intreatment studies; this tool is helpful in both interpretingthe data and formulating an approach to treatment of PAN.However, the FFS is based upon mortality and is notdesigned to predict either relapse or long-term morbidity,both of which are also important outcomes that influencetreatment decisions in PAN.There is no diagnostic laboratory test for PAN. Labo-

ratory tests can help determine the extent of organsaffected and their degree of involvement. These include

serum creatinine, muscle enzyme concentrations, liverfunction studies, HBV and hepatitis C virus serologies,and urinalysis. Acute-phase proteins are typically elevated,as evidenced by increased erythrocyte sedimentation rateand C-reactive protein concentrations, but are neithersensitive nor specific enough for the diagnosis of PAN tosubstantially affect diagnostic decision making.Blood cultures should be obtained in all patients

suspected of having a systemic vasculitis to excludeendovascular infection. Additional laboratory testing isvaluable in narrowing the differential diagnosis. Theseinclude the following assays, depending upon the alter-native diagnoses being considered based upon the patients'signs and symptoms: ANCA, antinuclear antibody, C3 andC4, cryoglobulins, serum and urine immunofixationelectrophoresis to test for monoclonal gammopathy, andtesting for human immunodeficiency virus.The American College of Rheumatology has established

10 criteria for the classification of PAN in a patient with avasculitis.12 The sensitivity and the specificity for thediagnosis of polyarteritis is 82% and 87%, respectively,in the patient with a documented vasculitis in whom atleast 3 of the following criteria are present: otherwiseunexplained weight loss greater than 4 kg, livedo retic-ularis, testicular pain or tenderness, myalgias (excludingthat of the shoulder and hip girdle), weakness of muscles,tenderness of leg muscles, mononeuropathy or polyneur-opathy, new-onset diastolic blood pressure greater than90 mm Hg, elevated levels of serum blood urea nitrogen(440 mg/dL or 14.3 mM/L) or creatinine (41.5 mg/dL or132 μM/L), evidence of HBV infection via serum antibodyor antigen serology, characteristic arteriographic abnor-malities not resulting from noninflammatory disease

Figure 3 A 60-year-old man who developed acute onset of burning paresthesias in his toes and feet followed byblistering ischemic lesions involving his toes with skin breakdown, splinter hemorrhages involving his fingers, andswelling involving his right third finger. The results of ANCA serology tests were negative. Angiogram of both thehands demonstrates segmental narrowing and microaneurysms (red arrows). (Color version of figure is availableonline.)

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processes, biopsy of small- or medium-sized artery con-taining polymorphonuclear cells. Glucocorticoids remainthe first-line treatment with remission occurring in 50% ofpatients. With the addition of cyclophosphamides, remis-sion or cure approaches 90% of the patients. HBV-associated PAN requires the addition of antivirals as well.Plasma exchange or plasmapheresis may have addedbenefit in refractory cases.

ImagingArteriography and cross-sectional imaging can be used asalternatives to tissue biopsy for the diagnosis and aretypically performed analyzing the mesenteric or renalcirculation.7 These studies can often be diagnostic, dem-onstrating multiple aneurysms and irregular constrictionsin the larger vessels with occlusion of smaller penetratingarteries (Figs. 1 and 2). Other findings can include multi-ple peripheral aneurysms of 1-5 mm, occlusions, irregularstenoses, and diffuse wall thickening of medium-sizedarteries (Figs. 1-4). For unknown reasons, PAN typicallyoccurs at small and medium vessel bifurcations. Locations

commonly involved include kidneys (70%-80%), GI tract,peripheral nerves, skin (50%), skeletal muscles and mes-entery (30%), and central nervous system (10%). Com-puted tomography (CT) and magnetic resonance (MR) areless invasive and provide evidence of end-organ damage,arterial wall thickening, and arterial occlusion.

Indications for the Procedure—When or When Not to Performthe ProcedureThe diagnosis of PAN is made based on the findings of thetissue biopsy or in conjunction with angiography. Rapiddiagnosis is necessary owing to progression of life-threatening complications such as acute renal failure, renalor perirenal hematoma, GI hemorrhage or perforation,liver infarct, and even cardiac failure. A patient withdecreased renal function is a relative contraindication forcontrast administration. In general, a glomerular filtrationrate greater than 60 mL/min should be considered safe. Aglomerular filtration rate of 30-60 mL/min should warrant

Figure 4 A 79-year-old woman with dissection (red arrow) of her superior mesenteric artery on sagittal CT (A) andaxial CT (B) with irregular narrowing (red arrow) of renal arteries (C). (Color version of figure is available online.)

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caution, and a reduced contrast agent dose and postpro-cedure intravenous fluids might help reduce the renaltoxic effects of contrast administration.

Care ContinuityPatients with cutaneous-only PAN or other single-organpresentations of PAN must also be followed regularly forthe possible development of disease in new organ systems.In addition to clinical examinations and appropriatefollow-up of patient-reported symptoms, periodic testingby measuring serum creatinine and a urinalysis can helpmonitor for asymptomatic renal disease. Erythrocytesedimentation rate and C-reactive protein may correlatewith disease activity. Follow-up angiography is notrequired unless there are signs or symptoms suggestiveof new disease, concerns for ischemia that may requireintervention, or aneurysms that are at risk for expansion orrupture and may require intervention. Depending on theanatomical location and size of affected arteries, MRimaging or CT angiography may be substituted forcatheter-based angiography. The choice of which imagingmodality (MR, CT, or catheter-based) to use will dependupon the availability of equipment and expertise at a

medical center and may be influenced by an interest inusing the same approach used for prior evaluations toallow for direct comparisons.

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4. Mahr A, Guillevin L, Poissonnet M, et al: Prevalences of polyarteritisnodosa, microscopic polyangiitis, Wegener's granulomatosis, andChurg-Strauss syndrome in a French urban multiethnic populationin 2000: A capture-recapture estimate. Arthritis Rheum 51:92-99,2004

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7. Balow JE: Renal vasculitis. Kidney Int 27:954-964, 19858. Frohnert PP, Sheps SG: Long-term follow-up study of periarteritis

nodosa. Am J Med 43:8-14, 1967

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9. Pagnoux C, Seror R, Henegar C, et al: Clinical features and outcomes in348 patients with polyarteritis nodosa: A systematic retrospective study ofpatients diagnosed between 1963 and 2005 and entered into the FrenchVasculitis Study Group Database. Arthritis Rheum 62:616-626, 2010

10. Guillevin L, Pagnoux C, Seror R, et al: The Five-Factor Scorerevisited: Assessment of prognoses of systemic necrotizing vasculi-tides based on the French Vasculitis Study Group (FVSG) cohort.Medicine 90:19-27, 2011

11. Bourgarit A, Le Toumelin P, Pagnoux C, et al: Deaths occurringduring the first year after treatment onset for polyarteritis nodosa,microscopic polyangiitis, and Churg-Strauss syndrome: A retrospec-tive analysis of causes and factors predictive of mortality based on595 patients. Medicine 84:323-330, 2005

12. Lightfoot RW Jr, Michel BA, Bloch DA, et al: The American Collegeof Rheumatology 1990 criteria for the classification of polyarteritisnodosa. Arthritis Rheum 33:1088-1093, 1990