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BOTTOM LINE

Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis affecting medium-sized muscular arteries and occasionally small muscular arteries most commonly supplying kidneys, skin, joints, muscles, nerves, and GI tract; lungs are usually spared.  PAN variants include single-organ disease—cutaneous PAN. PAN is not associated with antibody positivity. Treatment of mild disease includes steroids often combined with Azathioprine, methotrexate, or mycophelolate mofetil. Severe disease causing significant organ dysfunction is treated with cyclophosphamide. Patients with mild PAN associated with Hepatitis B/C infection may be treated with antivirals initially, with steroids and plasma exchange reserved for severe cases.
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EPIDEMIOLOGY

True idiopathic systemic PAN is rare; diseases previously called PAN have more recently been identified and classified as other forms of vasculitis (ex: ANCA-associated vasculitis, DADA2, vasculitis associated with drug exposure or infection)

• Prevalence and Incidence in European countries
  • Prevalence: ~30/1,000,000
  • Incidence ~0-9/1,000,000 annually
• Sex
  • Slight male predominance 1.5:1.0
• Age
  • Peak age 40-60 years-old
  • DADA2: Young patients presenting with PAN-like features and stroke or family history of early strokes should be screened for deficiency of adenosine deaminase 2 (DADA2)
• Hepatitis B
  • Hepatitis B association: historically as high as 10-30%, depending on series.
  • Association with PAN is declining alongside declining Hepatitis B prevalence in population, now associated in <5% of PAN

CLINICAL MANIFESTATIONS

—Clinical Variants

“Classic” PAN	Idiopathic systemic generalized medium/small vessel necrotizing arteritis affecting multiple organs
Hepatitis B-associated PAN	Medium-vessel necrotizing systemic arteritis associated with hepatitis B infection
Cutaneous PAN	Skin-limited medium vessel vasculitis, typically presenting in lower limbs

—Systemic Manifestations

• Systemic (93%)
  • Fatigue, weight loss, fever
• Neurological (75%)
  • Mononeuritis multiplex (70%), polyneuropathy (75%), CNS (5%)
• Musculoskeletal (~50%)
  • Arthralgias 49%, myalgias 58%
• Dermatological (50%)
  • Livedo reticularis, purpura, cutaneous nodules, ulcers mainly in lower extremities
• Renal (50%)
  • Renovascular hypertension (35%, severe 7%), infarct, AKI, minimal proteinuria and hematuria
• Gastrointestinal (38%)
  • Abdominal pain (35%), bleeding and perforation (3%), cholecystitis, appendicitis, pancreatitis, splenic infarct
• Genitourinary (17%)
  • Orchitis: testicular pain, swelling, infarction; more common with hepatitis B
• Cardiovascular (22%)
  • Cardiomyopathy (7.5%), coronary arteritis/MI, pericarditis, limb claudication, digital ischemia ±necrosis, VTE/DVT
• Ocular (10%)
  • Retinal vasculitis (4.3%), optic ischemia, conjunctivitis, episcleritis, keratitis, uveitis
• Ear, Nose, Throat
  • Hearing loss, temporal arteritis
• Respiratory
  • PAN does not typically affect the lungs; lung involvement may suggest an alternate diagnosis
• Other history
  • Drug history (?drug induced)
  • Exposure history (?hepatitis B, bacterial endocarditis)
  • Family history of early strokes (?DADA2)
  • Other rheumatic diseases (RA, SLE, ANCA vasculitis)

INVESTIGATIONS

—Laboratory Testing

No diagnostic bloodwork, but needed to screen the extent of systemic involvement and evaluate alternate diagnoses

• CBC
  • May show anemia of chronic inflammation or iron deficiency if GI bleeding/ischemia
• ALT
  • Usually normal
• Creatinine, urinalysis
  • ↑Cr if renal artery involved. U/A may show mild proteinuria/hematuria, no casts (i.e.: no glomerulonephritis)
• ESR, CRP
  • Usually elevated
• C3, C4
  • Should be normal
• Antibodies
  • No antibody association; negative ANA, RF, ANCA (unless positive by chance)
• Infectious
  • Hepatitis B and C serology.
  • Blood cultures (?septic emboli differential)
  • HIV: If mononeuritis multiplex and co-infected Hepatitis B or C
  • Lyme serology: if mononeuritis multiplex and Lyme exposure on history
• Other rheumatological disease, if indicated
  • Cryoglobulins, phospholipid antibodies,
  • Plasma ADA2 activity assay and genetic testing for CECR1 mutation on chromosome 22q11.1
    • Test if pediatric PAN, family history of early-onset strokes, atypical immunodeficiency with autoimmunity and/or lymphoproliferation

—Imaging

• X-ray
  • Screening X-ray chest: parenchymal lung involvement may suggest alternate diagnosis
• Conventional arteriography
  • Medium vessel saccular/fusiform microaneurysms (15mm in diameter) with co-existent stenoses.
  • Predominantly mesenteric, renal and hepatic arteries
  • Sensitivity and Specificity 90% invasive with risk of bleeding, embolization, and pseudoaneurysm
• CT or MR Angiography
  • Similar findings to Conventional Arteriography, though may not detect smaller microaneurysms
  • Benefit of imaging for ischemic parenchymal changes (ex: bowel, renal infarcts)

—Histology

• Common Targets
  • Skin (including subcutaneous fat with medium-sized arteries)
  • Nerve (sural, superficial peroneal, superficial radial)
  • Muscle+/-Nerve (muscle less sensitive).
• Findings
  • Focal, segmental, panmural necrotizing inflammation of medium muscular arteries (small vessels may be involved in addition)
  • Infiltrate of lymphocytes, macrophages, variable number of neutrophils and eosinophils
  • Predilection for bifurcations and branch points. Granuloma and giant cells should be absent.
• Other
  • Functional ADA2 assay and genetic testing for CECR1 mutation on chromosome 22q11.1
  • Test if pediatric PAN, family history of early-onset strokes, atypical immunodeficiency with autoimmunity and/or lymphoproliferation

DIAGNOSIS

PAN is rare but should be suspected in a patient, more often middle-aged, presenting with marked systemic symptoms and organ dysfunction reasonably explained by medium-sized vascular lesions (ex: livedo, necrotic skin ulcers, peripheral neuropathy, ischemic colitis, hypertension with hematuria/proteinuria without casts). PAN involving a single organ, such as cutaneous PAN, may also occur. Demonstration of micro-aneurysms on vascular imaging is the hallmark of PAN; consider abdominal vascular
imaging in patients with suspected PAN. Diagnosis is ideally confirmed with biopsy revealing focal and segmental transmural necrotizing vasculitis of medium-sized muscular arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Common biopsy targets of a symptomatic organ are deep skin, nerve, or combined nerve/muscle biopsy.

DIFFERENTIAL DIAGNOSIS

Any disease that can cause aneurysms and embolism/thrombosis/vasospasm

• Infectious
  • Viral: HBV, CMV, HTLV1, HIV, EBV, HCV
  • Bacterial: endocarditis with distal emboli
  • Fungal: mycotic aneurysm  with distal emboli
• Cardiovascular
  • Atherosclerosis
  • Embolic diseases: atrial myxoma, cholesterol crystals
• Rheumatological
  • Vasculitis: ANCA-associated, IgA vasculitis, cryoglobulinemic vasculitis, Cogan’s, FMF-associated, DAD2, SAVI
  • Systemic rheumatic disease: SLE, RA, idiopathic inflammatory myopathy,
• Drug-related
  • Including allopurinol, minocycline, propylthiouracil, amphetamines, ergotism
• Hematological
  • Anti-phospholipid antibody syndrome
  • Malignancy hair cell leukemia
• Other
  • Segmental arterial mediolysis (SAM): noninflammatory arterial disease looks like PAN on angiogram.
  • Patients present with life-threatening hemorrhages for aneurysmal rupture.
  • Ehlors-Danlos, fibromuscular dysplasia (cause of aneurysms)
  • Immunodeficiency:  Including deficiency in RAG1, RAG2, or TAP

CLASSIFICATION CRITERIA

PAN is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

ACR CRITERIA 1990

• Unexplained weight loss ≥4 kg
• Livedo reticularis
• Testicular pain/tenderness
• Myalgias (excluding shoulder and hip girdle), or weakness of muscles, or tenderness of leg muscles
• Mononeuropathy or multiple mononeuropathy or polyneuropathy
• New diastolic blood pressure >90 mmHg
• Elevated BUN (>14.3 mmol/L) or creatinine (>132 umol/L)
• Hepatitis B virus infection
• Angiographic evidence of aneurysms/occlusions of visceral arteries not due to atherosclerosis, fibromuscular dysplasia, or other noninflammatory cause
• A biopsy of small- or medium-sized artery containing polymorphonuclear cells

Patient is classified as PAN if ≥3 of 10 criteria present. Sensitivity 82%, Specificity 86%

TREATMENT

—Severe PAN

Severe PAN: Vasculitis with life- or organ-threatening manifestations (e.g., renal disease, mononeuritis multiplex, muscle disease, mesenteric ischemia, coronary involvement, limb/digit ischemia, five-factor score ≥1)

• Induction
  • Methylprednisolone 0.5-1.0g IV daily x 3  (if organ/life-threatening disease), or/then
  • Prednisone 1mg/kg/day (max 60-80mg/d) for 4 weeks with taper over 6-8 months, and
  • Cyclophosphamide (CYC), various options for induction:
    • CYC 15mg/kg IV week 0, 2, 4 then every 3 weeks for 3-6 months (until 3 months post-remission, max 1.2g)
    • CYC  1.5-2mg/kg/day PO for 3 months (until remission), then 1.5mg/kg/day x 3 months (max 200mg)
    • Remember to dose-reduce CYC for renal function and age
  • If unable to tolerate Cyclophosphamide
    • Methotrexate 20-25mg/week, or
    • Azathioprine 2mg/kg/d, or
    • Mycophenolate mofetil 1.0-1.5g BID (MMF is less well studied in PAN)
• Maintenance
  • Azathioprine 2mg/kg/d, or
  • Methotrexate 20-25mg/week, or
  • Mycophenolate mofetil 1000-1500mg BID
  • Duration: at least 18 months

—Non-severe PAN

Non-severe PAN: Vasculitis without life- or organ-threatening manifestations (e.g., mild systemic symptoms, uncomplicated cutaneous disease, mild inflammatory arthritis)

• Induction and Maintenace
  • Prednisone 0.5-1.0mg/kg/day for 2-4 weeks with taper over 6 months, and
  • Methotrexate 20-25mg/week, or
  • Azathioprine 2mg/kg/d, or
  • Duration: at least 18 months

—Specific cases

• Cutaneous PAN
  • Mild
    • Nodules, livedo: NSAIDs, colchicine
  • Moderate
    •  Pain, ulceration, necrosis: Prednisone ≤30mg/day with taper plus NSAIDs, colchicine hydroxychloroquine dapsone, methotrexate, or azathioprine
• DADA2
  • Prednisone 1mg/kg/day (max 60-80mg/d) with taper over 6-8 months, and
  • TNF inhibition (ex: infliximab, adalimumab)
• Hepatitis B or C related
  • Targeted anti-viral therapy
  • If necessary for severe disease:
    • Prednisone 1mg/kg/day x 2 weeks only (can worsen viral infection)
    • Plasma exchange
• Adjunctive
  • Physiotherapy: if nerve, muscle involvement
  • PCP prophylaxis: Sulfamethoxazole/trimethoprim if on cyclophosphamide and steroids
  • Gastric ulcer prophylaxis: PPI if on steroids
  • Osteoporosis prophylaxis: bisphosphonate if indicated

PROGNOSIS

• Five-year relapse-free survival
  • 59% for non-HBV-related PAN
  • 67.0% for HBV-related PAN
  • Higher relapses seen in non-HBV related PAN and cutaneous PAN
• Risk factors for mortality
  • Age >65 years,
  • Hypertension
  • Gastrointestinal manifestations requiring surgery or at least consultation
• Five-year mortality
  • 12% for patients with FFS = 0
  • 26% for patients with FFS = 1
  • 46% for patients with FFS ≥ 2

REFERENCES

Bourgarit, A., Toumelin, P. L., Pagnoux, C., Cohen, P., Mahr, A., Guern, V. L., Mouthon, L., Guillevin, L., & French Vasculitis Study Group (2005). 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, 84(5), 323–330. https://doi.org/10.1097/01.md.0000180793.80212.17

Chung, S. A., Gorelik, M., Langford, C. A., Maz, M., Abril, A., Guyatt, G., Archer, A. M., Conn, D. L., Full, K. A., Grayson, P. C., Ibarra, M. F., Imundo, L. F., Kim, S., Merkel, P. A., Rhee, R. L., Seo, P., Stone, J. H., Sule, S., Sundel, R. P., Vitobaldi, O. I., … Mustafa, R. A. (2021). 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa. Arthritis & rheumatology (Hoboken, N.J.), 73(8), 1384–1393. https://doi.org/10.1002/art.41776

De Virgilio, A., Greco, A., Magliulo, G., Gallo, A., Ruoppolo, G., Conte, M., Martellucci, S., & de Vincentiis, M. (2016). Polyarteritis nodosa: A contemporary overview. Autoimmunity reviews, 15(6), 564–570. https://doi.org/10.1016/j.autrev.2016.02.015

Hasler, P., Kistler, H., & Gerber, H. (1995). Vasculitides in hairy cell leukemia. Seminars in arthritis and rheumatism, 25(2), 134–142. https://doi.org/10.1016/s0049-0172(95)80026-3

Hernández-Rodríguez, J., Alba, M. A., Prieto-González, S., & Cid, M. C. (2014). Diagnosis and classification of polyarteritis nodosa. Journal of autoimmunity, 48-49, 84–89. https://doi.org/10.1016/j.jaut.2014.01.029

Hočevar, A., Tomšič, M., & Perdan Pirkmajer, K. (2021). Clinical Approach to Diagnosis and Therapy of Polyarteritis Nodosa. Current rheumatology reports, 23(3), 14. https://doi.org/10.1007/s11926-021-00983-2

Lightfoot, R. W., Jr, Michel, B. A., Bloch, D. A., Hunder, G. G., Zvaifler, N. J., McShane, D. J., Arend, W. P., Calabrese, L. H., Leavitt, R. Y., & Lie, J. T. (1990). The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis and rheumatism, 33(8), 1088–1093. https://doi.org/10.1002/art.1780330805

Morgan, A. J., & Schwartz, R. A. (2010). Cutaneous polyarteritis nodosa: a comprehensive review. International journal of dermatology, 49(7), 750–756. https://doi.org/10.1111/j.1365-4632.2010.04522.x

Ozen S. (2017). The changing face of polyarteritis nodosa and necrotizing vasculitis. Nature reviews. Rheumatology, 13(6), 381–386. https://doi.org/10.1038/nrrheum.2017.68

Pagnoux, C., Seror, R., Henegar, C., Mahr, A., Cohen, P., Le Guern, V., Bienvenu, B., Mouthon, L., Guillevin, L., & French Vasculitis Study Group (2010). 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 and rheumatism, 62(2), 616–626. https://doi.org/10.1002/art.27240