rheumatoid arthritis) Glomerulonephritis is much more typical of microscopic polyangiitis than PAN. Among patients with glomerulonephritis, the urinalysis typically has mild to moderate proteinuria, with an active sediment containing red cells and cellular and granular casts. (See "Glomerular disease: Evaluation and differential diagnosis in adults".) A mononeuropathy multiplex (or asymmetric polyneuropathy) with motor and sensory deficits is one of the most common findings in patients with PAN [25-27]. If present, this finding is highly suggestive of vasculitis; diabetic neuropathy is the only other common cause of this problem in developed countries [45]. Other forms of systemic vasculitis commonly associated with mononeuropathy multiplex are the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and mixed cryoglobulinemia. Also consider the presence of genetic disorders that have been associated with PAN: Adenosine deaminase deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis') https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 12/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome') Finally, with the increasing use and availability of cross-sectional abdominal imaging by CT or magnetic resonance (MR), more patients are being identified with incidentally discovered abnormalities of medium-sized arteries. Such patients may be labeled as having PAN, but clinicians need to be careful to avoid misdiagnosis of this rare disease based on radiographic data alone, especially without concomitant and physiologically concordant clinical manifestations of disease and/or evidence of change in arterial disease. Incidentally found medium-vessel disease is a quite difficult clinical scenario for which careful "watchful waiting" without treatment but with repeat imaging in three to six months may be appropriate. Classification criteria The American College of Rheumatology (ACR) has established ten criteria for the classification of polyarteritis nodosa in a patient with a vasculitis [46]. A sensitivity and specificity for the diagnosis of polyarteritis of 82 and 87 percent, respectively, has been found in the patient with a documented vasculitis in whom at least three of the following criteria are present: Otherwise unexplained weight loss greater than 4 kg Livedo reticularis Testicular pain or tenderness Myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg muscles, or polyneuropathy Mononeuropathy or polyneuropathy New-onset diastolic blood pressure greater than 90 mmHg Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 micromol/L) Evidence of hepatitis B virus infection via serum antibody or antigen serology Characteristic arteriographic abnormalities not resulting from noninflammatory disease processes ( image 1) A biopsy of small- or medium-sized artery containing polymorphonuclear cells PAN was defined by the Chapel Hill Consensus Conference (CHCC) as: "Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules" [47]. It is important to remember that neither the ACR Classification Criteria nor the CHCC nomenclature was meant to be used for the diagnosis of vasculitis [48]. Until validated https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 13/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate diagnostic criteria for PAN are established, the diagnosis of PAN is informed by the ACR and CHCC approaches but remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare disease. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis" and "Society guideline links: Polyarteritis nodosa".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Polyarteritis nodosa (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Definition and epidemiology Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with occasional involvement of small muscular arteries. The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN, particularly microscopic polyangiitis (MPA). Unlike MPA, PAN is not associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). The diagnosis is most commonly made in middle-aged or https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 14/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate older adults, and the incidence rises with age, with a peak in the sixth decade of life. (See 'Introduction' above and 'Epidemiology' above.) Etiology, pathogenesis, and pathology Most cases of PAN are idiopathic, although hepatitis B virus infection, hepatitis C virus infection, and hairy cell leukemia are important in the pathogenesis of some cases, which are termed secondary PAN. The pathogenetic mechanisms in PAN are poorly understood. It seems likely that, in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity. Regardless of the underlying cause, established PAN is characterized by segmental transmural inflammation of muscular arteries; it does not involve veins, unlike other forms of systemic vasculitis. (See 'Etiology' above and 'Pathogenesis' above and 'Pathology' above.) Clinical features Patients with PAN typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement ( table 1). (See 'Clinical features' above.) Diagnosis A clinical diagnosis of PAN is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and because of the potentially severe adverse effects related to treatment, the diagnosis should be confirmed by biopsy whenever possible. In the absence of an obvious site for biopsy, angiography sometimes reveals microaneurysms of blood vessels in the renal, hepatic, or mesenteric circulations. (See 'Diagnosis' above.) Classification criteria The diagnosis of PAN is informed by the classification criteria developed by the American College of Rheumatology and by the definitions and nomenclature of the Chapel Hill Consensus Conference, but there are no validated diagnostic criteria for PAN. Thus, the diagnosis remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare disease. (See 'Classification criteria' above.) Differential diagnosis The differential diagnosis of PAN is broad, including infectious diseases that affect the vasculature or that are complicated by systemic vasculitis; noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm; and other systemic vasculitides. (See 'Differential diagnosis' above.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 15/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Balow JE. Renal vasculitis. Kidney Int 1985; 27:954. 2. Sato O, Cohn DL. Polyarteritis and microscopic polyangiitis. In: Rheumatology, Klippel JH, Di eppe PA (Eds), Mosby, St Louis 2003. 3. Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46:1. 4. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum 2010; 62:616. 5. 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Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014; 370:921. 16. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370:911. 17. Schnappauf O, Sampaio Moura N, Aksentijevich I, et al. Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2. Arthritis Rheumatol 2021; 73:512. 18. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020; 383:2628. 19. Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol 2017; 13:381. 20. Stockigt JR, Topliss DJ, Hewett MJ. High-renin hypertension in necrotizing vasculitis. N Engl J Med 1979; 300:1218. 21. Ng WF, Chow LT, Lam PW. Localized polyarteritis nodosa of breast report of two cases and a review of the literature. Histopathology 1993; 23:535. 22. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin North Am 1995; 21:1097. 23. Karlsberg PL, Lee WM, Casey DL, et al. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia. Arch Dermatol 1995; 131:1119. 24. Leavitt RY, Fauci AS. Polyangiitis overlap syndrome. Classification and prospective clinical experience. Am J Med 1986; 81:79. 25. Ohkoshi N, Mizusawa H, Oguni E, Shoji S. Sural nerve biopsy in vasculitic neuropathies: morphometric analysis of the caliber of involved vessels. J Med 1996; 27:153. 26. Tervaert JW, Kallenberg C. Neurologic manifestations of systemic vasculitides. Rheum Dis Clin North Am 1993; 19:913. 27. Moore PM. Neurological manifestation of vasculitis: update on immunopathogenic mechanisms and clinical features. Ann Neurol 1995; 37 Suppl 1:S131. 28. Provenzale JM, Allen NB. Neuroradiologic findings in polyarteritis nodosa. AJNR Am J Neuroradiol 1996; 17:1119. 29. Cohen RD, Conn DL, Ilstrup DM. Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 1980; 55:146. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 17/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate 30. Reichart MD, Bogousslavsky J, Janzer RC. Early lacunar strokes complicating polyarteritis nodosa: thrombotic microangiopathy. Neurology 2000; 54:883. 31. Pagnoux C, Mahr A, Cohen P, Guillevin L. Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore) 2005; 84:115. 32. Zizic TM, Classen JN, Stevens MB. Acute abdominal complications of systemic lupus erythematosus and polyarteritis nodosa. Am J Med 1982; 73:525. 33. Levine SM, Hellmann DB, Stone JH. Gastrointestinal involvement in polyarteritis nodosa (1986-2000): presentation and outcomes in 24 patients. Am J Med 2002; 112:386. 34. Flaherty J, Bradley EL 3rd. Acute pancreatitis as a complication of polyarteritis nodosa. Int J Pancreatol 1999; 25:53. 35. Kastner D, Gaffney M, Tak T. Polyarteritis nodosa and myocardial infarction. Can J Cardiol 2000; 16:515. 36. Plumley SG, Rubio R, Alasfar S, Jasin HE. Polyarteritis nodosa presenting as polymyositis. Semin Arthritis Rheum 2002; 31:377. 37. Fort JG, Griffin R, Tahmoush A, Abruzzo JL. Muscle involvement in polyarteritis nodosa: report of a patient presenting clinically as polymyositis and review of the literature. J Rheumatol 1994; 21:945. 38. Teichman JM, Mattrey RF, Demby AM, Schmidt JD. Polyarteritis nodosa presenting as acute orchitis: a case report and review of the literature. J Urol 1993; 149:1139. 39. Akova YA, Jabbur NS, Foster CS. Ocular presentation of polyarteritis nodosa. Clinical course and management with steroid and cytotoxic therapy. Ophthalmology 1993; 100:1775. 40. Hsu CT, Kerrison JB, Miller NR, Goldberg MF. Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina 2001; 21:348. 41. Boki KA, Dafni U, Karpouzas GA, et al. Necrotizing vasculitis in Greece: clinical, immunological and immunogenetic aspects. A study of 66 patients. Br J Rheumatol 1997; 36:1059. 42. Jennette JC, Falk RJ. The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994; 24:130. 43. Kato T, Fujii K, Ishii E, et al. A case of polyarteritis nodosa with lesions of the superior mesenteric artery illustrating the diagnostic usefulness of three-dimensional computed tomographic angiography. Clin Rheumatol 2005; 24:628. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 18/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate 44. Schmidt WA. Use of imaging studies in the diagnosis of vasculitis. Curr Rheumatol Rep 2004; 6:203. 45. Hellmann DB, Laing TJ, Petri M, et al. Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases. Medicine (Baltimore) 1988; 67:145. 46. 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; 33:1088. 47. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. 48. Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis is it time to reclassify? Rheumatology (Oxford) 2011; 50:643. Topic 8245 Version 33.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 19/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate GRAPHICS Clinical manifestations of systemic polyarteritis nodosa Manifestation Frequency, percent Systemic symptoms 80 Fever, malaise, weight loss Neuropathy 75 Mononeuritis multiplex, polyneuropathy Arthralgias and/or myalgias 60 Articular and/or diffuse extremity pain Cutaneous 50 Livedo reticularis, purpura, ulcers Renal disease 50 Elevated creatinine, hematuria, glomerulonephritis Gastrointestinal symptoms 40 Abdominal pain, rectal bleeding Hypertension 35 New onset Respiratory manifestations 25 Infiltrates, nodules, cavities Central nervous system disease 20 Stroke, confusion Orchitis 20 Testicular pain, swelling Cardiac involvement 10 Cardiomyopathy, pericarditis Peripheral vascular disease 10 Claudication, ischemia, necrosis Adapted from: Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa. Arthritis Rheum 2010; 62:616. Graphic 53997 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 20/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Leukocytoclastic vasculitis Leukocytoclastic vasculitis appearing as raised purpura. This lesion can occur with any vasculitic syndrome and in the collagen vascular diseases. Courtesy of Marvin I Schwarz, MD. Graphic 78697 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 21/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Polyarteritis nodosa Light micrograph of a small muscular renal artery in polyarteritis nodosa. There is diffuse inflammation of the adventitia and marked thickening of the inner layers by loose connective tissue (arrows). The lumen (L) is significantly narrowed. Involvement of a vessel this large would be unusual in microscopic polyarteritis or granulomatosis with polyangiitis. Courtesy of Helmut Rennke, MD. Graphic 74893 Version 5.0 Normal glomerulus Light micrograph of a normal glomerulus. There are only one or two cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 22/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke, MD. Graphic 75094 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 23/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Kidney arteriogram in polyarteritis nodosa Kidney arteriogram in large-vessel polyarteritis nodosa showing characteristic microaneurysms (small arrows) and abrupt cutoffs of small arteries (large arrows). From: Rose BD. Pathophysiology of Renal Disease, 2d ed, McGraw-Hill, New York, 1987. Graphic 65987 Version 7.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 24/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Gene G Hunder, MD No relevant financial relationship(s) with ineligible companies to disclose. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 25/25