BASICS
DESCRIPTION
- Polyarteritis nodosa (PAN) is an antineutrophil cytoplasmic antibody (ANCA)-negative necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis of arterioles, capillaries, or venules (1).
- Involved systems include GI tract, peripheral nervous system (sensory and motor), central nervous system (CNS), renal (without glomerulonephritis), skin, testes/epididymis, heart (1,2 and 3)
- Features depend on location of vasculitis: mesenteric ischemia " “related symptoms, new onset or worsening hypertension, mononeuritis multiplex, purpuric or nodular skin lesions, or livedo reticularis (3).
- Renal disease in PAN usually manifests as hypertension (HTN) and mild proteinuria with/without azotemia. Renal infarction may occur (3).
- PAN formerly encompassed several distinct entities (classic PAN, microscopic PAN, cutaneous PAN). With the advent of ANCA testing, microscopic PAN appears unrelated to the other two, pathophysiologically.
- Patients with classic PAN are typically ANCA-negative (1,4).
- Patients with microscopic PAN have ANCAs directed against myeloperoxidase (MPO) and (generally) involvement of small arterioles (microscopic polyangiitis [MPA]). This is now classified as ANCA-associated vasculitis (1).
- Cutaneous (or limited) PAN is a chronic disease with cutaneous lesions with characteristic histopathologic features of PAN. There are few systemic manifestations, although myalgias and peripheral motor neuropathy (mononeuritis multiplex) or sensory neuropathy may be present. ANCA positivity is variable (5).
- Synonym(s): periarteritis; panarteritis; necrotizing arteritis
EPIDEMIOLOGY
Incidence
- Predominant age: Peak onset is in the 5th to 6th decade; incidence rises with age.
- 1.5:1 male predominance (6)
Prevalence
Rare: 2 to 33 cases/1 million adults (6) ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- Segmental, transmural, necrotizing inflammation of medium and small muscular arteries, with intimal proliferation, thrombosis, and ischemia of the organ/tissue supplied by the affected arteries. Aneurysm formation at vessel bifurcations (3)
- Hepatitis B " “related PAN results in direct injury to the vessel due to viral replication or deposition of immune complexes, with complement activation and subsequent inflammatory response (3).
- Most cases are idiopathic; 20% are related to hepatitis B or C infection (7).
- In patients with PAN and hepatitis B, HBsAg has been recovered from involved vessel walls (7).
Genetics
Mutations of adenosine deaminase 2 (ADA 2) have been identified in families with PAN (8). ‚
RISK FACTORS
Hepatitis B infection >> hepatitis C infection (cutaneous PAN) (7) ‚
COMMONLY ASSOCIATED CONDITIONS
- Hepatitis B (strong association with classic PAN) (7)
- Hepatitis C (less strongly linked to cutaneous PAN)
- Hairy cell leukemia
- 27 existing case reports of systemic PAN following hepatitis B vaccination (9)
- Minocycline (symptoms resolve on stopping drug, reoccur if rechallenged) (10)
- Case reports also associating PAN with CMV infection, amphetamines, and interferon (11)
DIAGNOSIS
There are no formal diagnostic criteria for PAN (1,3). ‚
Suspect PAN in patients with the following: ‚
- Acute, sometimes fulminant multisystem disease with a relatively short prodrome (i.e., weeks to months)
- Vasculitic skin rash with sensorimotor symptoms/findings
- Recent-onset HTN with systemic symptoms
- Unexplained sensory and/or motor neuropathy with systemic symptoms
- Hepatitis B infection with multisystem disease
HISTORY
General: systemic symptoms with multiorgan involvement (3) ‚
- Constitutional symptoms (fever, weight loss, malaise)
- Organ-specific symptoms
- Focal muscular weakness/extremity numbness
- Myalgia and arthralgia
- Rash
- Recurrent postprandial pain, intestinal angina, nausea, vomiting, and bleeding
- Altered mental status, headaches, mononeuritis multiplex
- Testicular/epididymal pain, neurogenic bladder (rare)
PHYSICAL EXAM
Related to involved organ system (may dominate clinical picture and course)(2,3) ‚
- Peripheral nervous system: peripheral neuropathy
- Renal: HTN
- Skin: purpura, urticaria, polymorphic rashes, subcutaneous nodules (uncommon, but characteristic), livedo reticularis; deep skin ulcers, especially in lower extremities; Raynaud phenomenon (rare); single digit gangrene (rare)
- GI: acute abdomen; rebound, guarding, tenderness
- CNS: seizures, altered mental status, papillitis
- Lung: signs of pleural effusion " •dullness to percussion; decreased breath sounds
- Cardiac: signs of congestive heart failure and/or myocardial infarction " •S3 gallop; pericarditis (friction rub is rare)
- Genitourinary: testicular/epididymal tenderness (can mimic testicular torsion)
- Musculoskeletal: arthritis (usually large joint in lower extremities)
DIFFERENTIAL DIAGNOSIS
- Other forms of vasculitis (ANCA-associated, such as GPA, Churg-Strauss syndrome, and MPA; Henoch-Sch ƒ ¶nlein purpura, drug-induced vasculitis, cryoglobulinemia, Goodpasture syndrome)
- Buerger disease
- Systemic lupus erythematosus (SLE)
- Embolic disease (atrial myxoma, cholesterol emboli)
- Thrombotic disease (antiphospholipid antibody syndrome)
- Dissecting aneurysm
- Ehlers-Danlos syndrome
- Multiple sclerosis, systemic amyloidosis
- Infection (subacute endocarditis, HIV infection, trichinosis, rickettsial diseases)
DIAGNOSTIC TESTS & INTERPRETATION
- No specific laboratory abnormalities. Confirm diagnosis with biopsy if possible (4)[C].
- Angiography (conventional, CT angiography, or MR angiography) may reveal microaneurysms and/or beading of bifurcating blood vessels.
- Avoid contrast in renal disease.
- Nonspecific laboratory abnormalities:
- Elevated ESR and CRP
- Mild proteinuria, elevated creatinine
- Hepatitis B surface antigen positive in 10 " “50%
- Hepatitis C antibody/hepatitis C virus RNA
- ANCA, antiproteinase 3 (PR3), and anti-MPO are negative. Positive ANCA argues against PAN.
- Rheumatoid factor may be positive.
- Anemia of chronic disease (3,4):
Initial Tests (lab, imaging)
Lab tests performed to look for evidence of systemic disease and rule out other causes (3,4) are as follows: ‚
- CBC, ESR, CRP (elevated) (4)[C]
- Chemistries: elevated creatinine/BUN (4)[C]
- Hepatitis B serology: often positive; hepatitis C less commonly positive
- LFTs: abnormal if involving the liver/biliary tract
- Urinalysis: proteinuria/hematuria, generally no cellular casts or active urinary sediment (4)[C]
- ANA, cryoglobulins (4)[C]
- ANCA, anti-MPO, and anti-PR3 (4)[A]
- Complement levels (C3, C4)
- Angiographic demonstration of aneurysmal changes/beading of small and medium-sized arteries
Diagnostic Procedures/Other
- Electromyography and nerve conduction studies in patients with suspected mononeuritis multiplex. If abnormal, consider sural nerve biopsy.
- Arterial/tissue biopsy
- Skin biopsy from edges of ulcers; include deep dermis and subcutaneous (SC) fat to assess small muscular artery involvement (excisional not punch biopsy) (3,4)
Test Interpretation
- Necrotizing inflammation with fibrinoid necrosis of small and medium-sized muscular arteries; segmental, often at bifurcations and branchings. Venules not involved in classic PAN.
- Capillaritis/other lung parenchymal involvement by vasculitis strongly suggests another process (microscopic PAN, granulomatosis with polyangiitis [GPA; formerly known as Wegener granulomatosis], Churg-Strauss syndrome, or antiglomerular basement membrane disease).
- Acute lesions with infiltration of polymorphonuclear cells through vessel walls into perivascular area; necrosis, thrombosis, infarction of involved tissue
- Aneurysmal dilatations, including aortic dissection
- Peripheral nerves: 50 " “70% (vasa nervorum with necrotizing vasculitis)
- GI vessels: 50% (at autopsy) with bowel necrosis; gallbladder and appendix vasculature: 10%
- Muscle vessels: 50%
- Testicular vessels involved in symptomatic males
- The key differences from other necrotizing vasculitides are lack of granuloma formation and sparing of veins and pulmonary arteries (2,3).
TREATMENT
GENERAL MEASURES
Aggressively treat HTN to prevent associated complications (stroke, myocardial infarction, heart failure) ‚
MEDICATION
First Line
- Severe (life-threatening) disease: corticosteroids (CS) (high-dose prednisone, methylprednisolone or parenteral Solu-Medrol) (4,10)[A]
- Only 50% of patients achieve and maintain remission with CS. Other patients require additional immunosuppressive therapy.
- Cyclophosphamide (CTX) in combination with CS: improves survival and spares use of chronic steroids in moderate/severe PAN (4,10)[A]
- CTX has risk of infertility and malignancy.
- Plasma exchange for refractory and renal disease (4,7)[A]
- Rituximab use for refractory disease suggested by its efficacy in ANCA+ vasculitis (4,12,13)[C].
- Less severe disease: CS alone ‚ ± other immunosuppressive agents(azathioprine, (4)[A] methotrexate, mycophenolate mofetil (4,10,14)[B])
- HBV-associated PAN: antiviral agents, short-term CS, plasma exchange (7,10)[C]
Second Line
- Tumor necrosis factor inhibitors anecdotally reported to be of use in PAN (15)
- PAN disease activity correlates with serum IL-6 levels; tocilizumab, an inhibitor of IL-6 approved for use in rheumatoid arthritis; no evidence-based data for PAN (16).
ADDITIONAL THERAPIES
- For patients receiving IV CTX, concurrent administration of mercaptoethane sulfonate reduces bladder exposure to carcinogenic metabolites (4)[C].
- Prophylactically treat patients on CTX for Pneumocystis jiroveci (carinii) pneumonia with trimethoprim sulfamethoxazole (use dapsone or atovaquone in intolerant/allergic patients) (4).
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Depends on extent and involvement of specific organs ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- CBC, urinalysis, renal and hepatic function tests
- Acute-phase reactants (e.g., ESR, CRP) may help monitor disease activity.
- Be alert for the following:
- Treatment specific side effects of CS and immunosuppressant medications
- Delayed appearance of neoplasms after treatment, especially bladder malignancy in patients treated with CTX. (Check annual U/A, urinary cytology with urologic evaluation if microscopic hematuria.) (4)[C]
- Steroid-induced osteoporosis
DIET
Low salt (HTN) ‚
PATIENT EDUCATION
- Patient education materials are available from the Arthritis Foundation, 1314 Spring St, NW, Atlanta, GA 30309; 800-283-7800
- ACR website: www.rheumatology.org
PROGNOSIS
- Expected course of untreated PAN is poor, with an estimated 5-year survival of 13% (17).
- Steroid and cytotoxic treatment increase 5-year survival rate to 75 " “80% (3,17).
- Survival is greater for hepatitis B " “related PAN as a result of the introduction of antiviral treatments (7).
- Patients presenting with proteinuria, renal insufficiency, GI tract involvement, cardiomyopathy, or CNS involvement have a worse prognosis.
COMPLICATIONS
- End-organ damage from ischemia
- Complications from immunosuppressive agents
REFERENCES
11 Jennette ‚ JC, Falk ‚ RJ, Bacon ‚ PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1 " “11.22 Ebert ‚ EC, Hagspiel ‚ KD, Nagar ‚ M, et al. Gastrointestinal involvement in polyarteritis nodosa. Clin Gastroenterol Hepatol. 2008;6(9):960 " “966.33 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(2):616 " “626.44 Mukhtyar ‚ C, Guillevin ‚ L, Cid ‚ MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68(3):310 " “317.55 Nakamura ‚ T, Kanazawa ‚ N, Ikeda ‚ T, et al. Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria. Arch Dermatol Res. 2009;301(1):117 " “121.66 Phillip ‚ R, Luqmani ‚ R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. 2008;26(5)(Suppl 51):S94 " “S104.77 Guillevin ‚ L, Mahr ‚ A, Callard ‚ P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313 " “322.88 Navon Elkan ‚ P, Pierce ‚ SB, Segel ‚ R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921 " “931.99 de Carvalho ‚ JF, Pereira ‚ RM, Shoenfeld ‚ Y. Systemic polyarteritis nodosa following hepatitis B vaccination. Eur J Intern Med. 2008;19(8):575 " “578.1010 Culver ‚ B, Itkin ‚ A, Pischel ‚ K. Case report and review of minocycline-induced cutaneous polyarteritis nodosa. Arthritis Rheum. 2005;53(3):468 " “470.1111 Bourgarit ‚ A, Le Toumelin ‚ P, Pagnoux ‚ C, et al. Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore). 2005;84(5):323 " “330.1212 de Menthon ‚ M, Mahr ‚ A. Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol. 2011;29(1)(Suppl 4):S110 " “S116.1313 Stone ‚ JH, Merkel ‚ PA, Spiera ‚ R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221 " “232.1414 Specks ‚ U, Merkel ‚ PA, Seo ‚ P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417 " “427.1515 Ribi ‚ C, Cohen ‚ P, Pagnoux ‚ C, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one hundred twenty-four patients. Arthritis Rheum. 2010;62(4):1186 " “1197.1616 Chan ‚ M, Lugmani ‚ R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother. 2009;10(8):1273 " “1289.1717 Murakami ‚ M, Nishimoto ‚ N. The value of blocking IL-6 outside of rheumatoid arthritis: current perspective. Curr Opin Rheumatol. 2011;23(3):273 " “277.
ADDITIONAL READING
- Kouchi ‚ M, Sato ‚ S, Kamono ‚ M, et al. A case of polyarteritis nodosa associated with cytomegalovirus infection. Case Rep Rheumatol. 2014;2014:604874.
SEE ALSO
Hepatitis B; Hepatitis C ‚
CODES
ICD10
- M30.0 Polyarteritis nodosa
- M30.1 Polyarteritis with lung involvement [Churg-Strauss]
- M30.8 Other conditions related to polyarteritis nodosa
- M31.7 Microscopic polyangiitis
ICD9
446.0 Polyarteritis nodosa ‚
SNOMED
- 155441006 Polyarteritis nodosa (disorder)
- 239928004 microscopic polyarteritis nodosa (disorder)
- 239925001 Polyarteritis nodosa with single organ involvement
- 239927009 Polyarteritis nodosa with multi-organ involvement
- 239926000 Cutaneous polyarteritis nodosa
CLINICAL PEARLS
- PAN is a necrotizing vasculitis of small- to medium-sized muscular arteries with lack of granuloma formation that spares veins and pulmonary arteries.
- Clinical features of PAN depend on target organ involvement.
- Skin biopsies at ulcer edges (include deep dermis and SC fat) improve diagnostic yield.
- Check hepatitis B and C serologies.
- ANCA is negative in classic PAN.
- Treatment involves immunosuppression; choice of agent depends on extent and severity of disease.