A. Characteristics [1,2]

1. Inflammation affects medium and small arteries
   1. Usually in middle aged men
   2. ~70% patients have intra-renal aneurysms
2. Produces aneurysms at branching points
3. Patients usually very sick with significant systemic symptoms, malaise and weight loss
4. Should be distinguished from microscopic polyangiitis (see below)
5. Churg-Strauss Syndrome is a PAN varient with asthma, atopy, and eosinophilia

B. Pathophysiology

1. Anti-Neutrophil Cytoplasmic Antibody (ANCA)
   1. Most (>50%) patients have perinuclear ANCA pattern
   2. C-ANCA often positive if lungs are involved and/or with Wegener's Granulomatosis
   3. C-ANCA is much more common in Wegener's Granulomatosus (see below)
   4. P-ANCA is usually directed against Myeloperoxidase (MPO) in PAN
   5. P-ANCA may be found in Churg-Strauss disease and ~50% of IBD patients
   6. P-ANCA also found in rapidly progressive glomerulonephritis and other disease
   7. Titers of ANCA do not correlate with disease activity
   8. However, increasing ANCA levels may precede a disease flare
2. Type III Hypersensitivity: immune complexes implicated
3. Leukocytoclastic Vasculitis
   1. Leukocytoclasis and fibrinoid necrosis occurs in medium sized muscular arteris
   2. Destruction of internal and external elastic laminas with eventual transmural necrosis
   3. Macrophages and T lymphocytes (~40% of cases each)
   4. CD4+ T most common type of lymphocyte
   5. Granulocytes actually variable in numbers
4. Tissue inflammation and destruction: skin, nerve, muscle, others
5. Hepatitis B Virus (HBV) Infection and PAN [5]
   1. ~15% of cases are HBsAg+
   2. Usually have mildly increased transaminases
   3. PAN usually manifests within first 6 months of HBV infection
   4. Hepatitis C virus (HCV) may also be associated with PAN infrequently

C. Symptoms [5]

1. Systemic
   1. Fever
   2. Weakness and Malaise
   3. Weight Loss
2. Hypertension (HTN)
3. Renal Insufficiency
   1. May contribute to HTN
   2. Hematuria: active urinary sediment with red blood cells (RBC) and RBC casts
   3. Nephrotic syndrome uncommon
4. Cutaneous Involvement
   1. Ulcerations
   2. Palpable purpura
   3. Livedo reticularis
   4. Digital Tip Infarctions
5. Gastrointestinal (GI) [4]
   1. Nearly 50% of patients with PAN have GI symptoms
   2. Over 50% of these developed acute surgical abdominal complications
   3. Pain is most prominant symptom, likely due to mesenteric arterial disease
6. Peripheral Neuropathy
   1. 50-70% of patients
   2. Lower extermity sensory findings, usually pain
   3. Often mononeuritis multiplex
7. Testicular pain or tenderness
8. Lung Involvement [2]
   1. ANCA+ lung inflammation usually microscopic polyangiitis or Wegener's
   2. Microscopic polyangiitis involving lung is P-ANCA+ and
   3. Wegener's is typically C-ANCA+, anti-proteinase III Ab+, granulomas present
   4. Goodpasteur's with anti-basement membrane Abs should also be ruled out
   5. Initially, bilateral pneumonitis occurs with shortness of breath and dyspnea
   6. Reduced diffusing capacity (DLCO) and forced vital capacity (FVC)
   7. Alveolitis with pulmonary hemorrhage may occur
   8. CT scan may show "ground-glass appearance" of lung parenchyma
   9. Majority of P-ANCA+ patients with alveolar hemorrhage are anti-MPO+

D. Diagnosis [1,3]

1. P-ANCA positive >50% of cases of PAN
   1. >60% have anti-MPO Abs
   2. Persistently high titers of ANCA are correlated with disease relapses
   3. Increases in anti-MPO Ab titers predict relapses in >70% of patients
   4. P-ANCA (with MPO+) usually positive in microscopic polyangiitis
2. Skin Biopsy
   1. Focus on purpuric lesions
   2. Leukocytoclastic vasculitis (neutrophil infiltrates)
   3. IgA absent
3. Nerve - sural nerve biopsy can often help make diagnosis
4. Dilatations of medium arteries proximal to obstruction, diagnosed by angiography or MRA
5. Hematologic Changes
   1. WBC may be highly increased, 10-40K/µL
   2. Anemia of chronic disease is not uncommon
   3. Thrombocytosis as "acute phase reactant"
   4. ESR often highly increased
   5. Hypocomplementemia uncommon
6. Kidney biopsy uncommonly shows rapidly progressing glomerulonephritis

E. Treatment

1. Glucocorticoids
   1. Initial therapy 1-2mg/kg po prednisone or iv methylprednisolone
   2. Are not effective alone; cytotoxic therapy is nearly always required
   3. Severe glomerulonephritis may be treated with high dose (0.5-1gm iv) glucocorticoids
   4. Glucocorticoids are maintained for 3-6 months with taper and monitoring for relapse
2. Cyclophosphamide (Cytoxan®) [6]
   1. Best studied of the cytotoxic agents
   2. Very effective in preventing relapse of disease
   3. Indicated for glucocorticoid resistant disease or ANY major organ involvement
   4. Usually given 2mg/kg/day po initially with slow taper in 3-12 months
   5. May also be administered 0.6mg/m2 intravenously monthly
   6. Common side effects are neutropenia, anemia and hemorrhagic cystitis
   7. Low incidence of acute leukemia dependent on dose and duration of therapy
3. Azathioprine (Imuran®)
   1. Usually used in cyclophosphamide intolerant patients
   2. Clearly effective as maintenance therapy 2mg/kg for or patients in clinical remission after 3 months of cyclophosphamide [7]
   3. Unclear if weekly MTX is as effective, but is likely better tolerated
   4. Major side effects are allergies and neutropenia
   5. Typical dose usually 2-4mg/kg/po
4. Mycophenolate Mofetil (CellCept®)
   1. Relatively B-cell specific immunosuppressive agent
   2. Reduced ANCA titers in PAN and Wegener's patients [8]
   3. Dose is 1gm po bid
5. Hepatitis B Virus Associated PAN [5]
   1. In addition to immunosuppressives, antivirals should be considered
   2. Interferon alpha is currently the mainstay of therapy
   3. Lamivudine and other oral antivirals have good activity
6. Relapse
   1. Clinical signs (and symptoms) may predict relapse
   2. Increased ANCA titers predicted relapse in many patients

F. Other Associated Syndromes

1. Churg-Strauss Syndrome
   1. Triad of severe asthma, hyper-IgE, eosinophilia >10%, and allergies
   2. Excellent response to glucocorticoids
   3. P-ANCA is positive in 30-50% of patients
   4. Granulomas with eosinophils are typical lung biopsy finding
2. Microscopic Polyangiitis [9]
   1. Inflammation of arterioles ± capillaries / venules
   2. Much more common than true PAN [1,2]
   3. Lung and kidney often involved
   4. Kidney lesions are necrotizing glomerulonephritis (~80%) usually with crescents
   5. P-ANCA in 55-90% of patients (anti-MPO Ab positive)
   6. Immunosuppressive treatment continued for 1 year after disease controlled / remission
   7. Combination glucocorticoids and cyclophosphamide very effective
   8. Concern about ovarian function with cyclophosphamide therapy
3. Hypersensitivity Angiitis
   1. Leukocytoclastic small vessel vasculitis
   2. Probably related to Henoch-Schnlein Purpura (HSP)
   3. Immune complex formation with IgA deposition
   4. Usually related to drug reaction
4. Lymphomatoid Granulomatosis
   1. Invasion of various tissues by PMNs in blood vessels
   2. Lymphocytes, histiocytes, plasma cells follow with granuloma formation
   3. Vascular occlusion and necrosis of tissue occur
   4. Lungs, kidneys, skin, CNS, often involved; PNS only ~7% of cases
   5. Lung lesions often cavitary
   6. Associated with development of fatal lymphoma
5. Cogan Syndrome
   1. Interstitial keratitis
   2. Inner ear infarction
   3. Systemic vasculitis often with aortic valve involvement
6. Kawasaki Disease
   1. Mucocutaneous lymph node syndrome - lymphadenopathy, rash, fevers
   2. Usually in children
   3. Medium and small artery involvement only
   4. Concern for development of aortic aneurysms
7. Kohlmeier-Degos Syndrome (Degos Disease) [10]
   1. Thrombotic vasculopathy of medium vessels
   2. Non-inflammatory vascular occlusive process mainly affecting arterioles
   3. Blood vessels with increased intima due to proliferation of endothelial cells
   4. Superimposed thrombus may occur
   5. Result is ischemia and infarction
   6. Most cases with skin involvement with small whitish nodules to pinkish papules
   7. Lymphatic obstruction
   8. Severe forms may affect central nervous system, gastrointestinal tract, submucosal arteries

References

1. Stone JH. 2002. JAMA. 288(13):1632
2. Seo P. 2002. Am J Med. 112(9):731 (Case Discussion)
3. Kyndt X, Remaux D, Bridoux F, et al. 1999. Am J Med. 106(5):527
4. Levine SM, Hellmann DB, Stone JH. 2002. Am J Med. 112(5):386
5. Coblyn JS and McCluskey RT. 2003. NEJM. 348(4):333 (Case Record)
6. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021
7. Jayne D, Rasmussen N, Andrassy K, et al. 2003. NEJM. 349(1):36
8. Nowack R, Birck R, van der Woude FJ. 1997. Lancet. 349:774
9. O'Sullivan BP, Erickson LA, Niles JL. 2002. NEJM. 347(13):1009 (Case Record)
10. Caviness VS Jr, Sagar P, Israel EJ, et al. 2006. NEJM. 355(24):2575 (Case Record)