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A. Definition and Incidence [1,10] navigator

  1. Key feature is Immunological Damage to Endothelium
    1. Arteritis is prominant
    2. Therefore, inflammation of arterials critical for diagnosis
    3. Venous system may be involved, but not primarily
    4. Must be idiopathic endothelial damage with lymphocytic involvement
    5. May not be directly related to acute infection, sepsis syndrome, or other acute incident
    6. Vascular endothelial damage leads to early end organ damage, chronic atherosclerosis
  2. Leukocyte/endothelial cell adhesion molecules are central to the vasculitic process [13]
  3. True Vasculitis requires:
    1. Exclude other inflammatory diseases where arteritis is not primary - SLE, RA, others
    2. Proof by angiography or preferably biopsy of arterial inflammatory changes
    3. For larger cell vasculitis, both arterial stenoses and dilatations are observed
    4. Rule out atherosclerotic disease (arterial stenoses predominate, some aneurysms)
  4. Excluding Giant Cell Arteritis, incidence of vasculitis is ~40 cases / million person-years [6]
    1. Giant Cell Arteritis 100-500 cases / million / year (~20,000 cases per year)
    2. Systemic Rheumatoid Vasculitis ~12 cases / million / year
    3. Wegener's Granulomatosis ~9 cases / million / year (~18,000 patients in USA)
    4. Churg-Strauss Syndrome ~2.5
    5. Microscopic Polyangiitis (PAN Variants) ~2.5
    6. Henoch-Schonlein Purpura ~1
    7. Isolated CNS Angiitis (vasculitis) is extremely uncommon

B. Presentation [1,2]navigator

  1. Symptoms and signs are varied and nonspecific
    1. Systemic: Fevers, Malaise, Weight Loss
    2. Abdominal pain (panniculitis, mesenteric ischemia)
    3. Discoloration of extremities
    4. Pain may occur due to neuropathy
  2. Classification of Vasculitis Syndromes [2]
    1. American College of Rheumatology (ACR) vasculitis criteria developed in 1990
    2. These 1990 ACR criteria have a 29-75% positive predictive value [3]
    3. Vasculitis groups classified by prominant symptoms and vessels affected
    4. Biopsy of affected tissue remains the gold standard for diagnosis
    5. 1994 Chapel Hill consensus divided vasculitis into large, medium, and small vessel families
  3. Aortitis (Large Vessel Vasculitis) Group
    1. Giant Cell (Temporal) Arteritis
    2. Takayasu Arteritis
    3. Cogan's Syndrome
    4. Large arteries involved
  4. Polyarteritis Nodosa (PAN) Group
    1. Classical PAN (medium vessel vasculitis)
    2. Microscopic PAN (small vessel vasculitis)
    3. Kawasaki Disease
    4. Kohlmeir-Degos Disease
    5. Involvement of medium sized arteries ± arterioles
  5. Purpura Group (Small Vessel Immune Complex Vasculitis) [16]
    1. Hypersensitivity (drug induced) vasculitis (including serum sickness) [4]
    2. Henoch-Schonlein Purpura (HSP)
    3. Mixed Cryoglobulinemia
    4. Sjogren's Syndrome: ~25% present with vasculitis (usually RF+, Ro+) [5]
    5. Small arteries involved
  6. Pulmonary Group (Small Vessel Pauci-Immune Vasculitis)
    1. Wegener's Granulomatosis
    2. Churg-Strauss Syndrome
    3. Microscopic polyangitits
    4. Small arteries involved with positive ANCA
  7. Miscellaneous Vasculitides
    1. Behcet's Disease (often ANCA+)
    2. Buerger's Disease (thromboangiitis obliterans)
    3. Paraneoplastic Vasculitis
    4. Isolated vasculitis of the CNS, including cerebral granulomatous angiitis (below)
    5. Panniculitis with vasculitis (erythema induratum, associated with tuberculosis) [8]
    6. Vasculitis associated with other connective tissue disease
  8. Anti-Neutrophil Antibody (ANCA) Vasculitis
    1. Wegener Granulomatosis
    2. Polyarteritis Nodosa (Classical PAN)
    3. Microscopic Polyangiitis (Small Vessel ANCA Positive PAN)
    4. Rapidly Progressive Crescentic Glomerulonephritis (RPGN)
    5. Behcet's Disease
    6. Churg-Strauss Syndrome

C. Laboratory navigator

  1. Markers of Inflammation
    1. Elevated ESR in nearly all cases
    2. C-reactive protein (CRP) also highly elevated and correlates with disease
    3. Cytokines typically elevated, particularly IL-6, IL-1ß, IL-1RA, others
    4. Elevated serum levels of soluble receptors prominant, including IL-2R, sCD30
  2. Hematologic Changes
    1. Leukocytosis usually with neutrophilia
    2. Anemia - usually of chronic disease
    3. Thrombocytosis - as an acut phase reactant
    4. Lymphocytes typically activated in peripheral blood
  3. Autoantibodies
    1. Best corellation with ANCA related disease
    2. Serology: ANA+ or RF+: Consider lupus, Sjogren Syndrome or rheumatoid vasculitis [5]
    3. These are secondary vasculitides
    4. Autoantibodies more important in medium and small vessel disease (not large vessel)
  4. Complement levels are often depressed
    1. Mainly true in immune complex and autoantibody related diseases
    2. Due to consumption of complement proteins due to antibody binding
  5. Activation of contact-system (prekallikrein) leads to bradykinin (BK) production [15]
    1. BK stimulates edema and reduces local blood pressures
    2. BK can also cause pain
  6. Circulating Endothelial Cells [11]
    1. Normal or large vessel vasculitis <20 endothelial cells/mL
    2. Elevated levels (median 136 cells/mL, 20-5700 cells/mL) in small vessel ANCA+ vasculitis
  7. Viral Infection and Vasculitis [9]
    1. Hepatitis B Virus infection is associated with ~50% of true PAN cases
    2. Hepatitis C Virus infection is associated with mixed cryoglobulinemia
    3. There are HIV-related vasculitic syndromes which are poorly understood

D. Characteristics [2]navigator

  1. Large Vessel
    1. Upper body involvement: aorta, carotids
    2. Blindness, syncope may occur
    3. Appears that T cells, macrophages, and endothelial cells play key roles
    4. Immune complexes and/or B cell dysfunction is less or not important
  2. Medium Vessel
    1. Multiple organ/system events
    2. Digital gangrene (Raynaud's Disease)
    3. Coronary Artery Disease: myocardial ischemia
    4. Renal Artery Disease: hypertension, renal insufficiency
    5. Claudication
    6. Mononeuritis multiplex (small peripheral strokes, abrupt onset)
    7. Cerebrovascular accident (CVA, Stroke)
    8. Appears that T cells and macrophages may directly damage endothelial cells
    9. Immune complexes and autoantibodies (B cells) also play important roles
    10. Thus, medium vessel vasculitides likely involve humoral and cellular inflammation
  3. Small Vessel
    1. Classically nail base area is affected, various skin lesions common
    2. Palpable purpura: tender red to purple bumps which does not blanch
    3. Raynaud's Disease may progress to necrosis and gangrene
    4. Cutaneous problem may involve swollen PIP joints
    5. Peripheral neuropathy, polyfocal neuralgia
    6. Renal dysfunction
    7. Antibodies and immune complexes appear to play key role in small vessel vasculitides
    8. T cells may play a role in helping B cell antibody production, but less directly damage
    9. Endothelial cell damage due to immune complex deposition, hyperviscosity, autoantibody
  4. Isolated Vasculitis (Angiitis) of the Central Nervous System (CNS) [7,12]
    1. Does not fit into any of the above categories (systemic symptoms do not occur)
    2. Pathology confined to brain and spinal cord within dura
    3. Acute or subacute presentation with focal, multifocal or diffuse CNS symptoms
    4. Pathology occurs due to vessel obliteration and ischemia
    5. Nonspecific inflammatory changes found in cerebrospinal fluid (CSF)
    6. Confirmatory diagnosis only possible by leptomeningeal and wedge cortical tissue biopsy
    7. Biopsy usually shows granulomatous inflammation of CNS small vessels
    8. Varicella zoster virus infection can also cause small or large vessel CNS vasculopathy [8]
    9. Treatment with combination glucocorticoids and cyclophosphamide are effective
    10. However, residua are common

E. Differential Diagnosisnavigator

  1. Small Vessel Vasculitis
    1. Infectious Endocarditis and Sepsis
    2. Infection: Gonnococci, Meningococci, Rickettsia, Toxic Shock, Pseudomonas, Candida
    3. Macroglobulinemia
    4. Acute Myelogenous and other Leukemias
    5. Myeloproliferative Disorders
    6. Atrial Myxoma - thromboemoblic disease
    7. Syphilis, AIDS
    8. Paraneoplastic Vasculitis
    9. Celiac Disease
  2. Medium Vessel Disease
    1. Cholesterol Emboli Syndrome
    2. Sinonasal Non-Hodgkin's Lymphoma
    3. Lymphomatoid Granulomatosis
  3. Large Vessel Disease
    1. Atherosclerotic Disease
    2. Thromboangiitis obliterans
  4. Panniculitis
    1. Erythema nodosum
    2. Nodular liquefying panniculitis (pancreatic panniculitis)
    3. Weber-Christian Disease
  5. Other
    1. Erythema multiforme
    2. Immune thrombocytopenia purpura
    3. Radiation injury

F. Therapy Overview navigator

  1. Prompt recognition is key to good prognosis
  2. Glucocorticoids
    1. Prednisone orally1-2mg/kg/day instituted in moderate disease
    2. Methylprednisolone 500-1000mg/d often given for severe renal, CNS, or ocular disease
  3. Cytotoxic Agents
    1. Cyclophosphamide 1-2mg/kg/day often given for moderate disease
    2. Azathioprine may be used in less severe cases, 2-4mg/kg/day
    3. Chlorambucil has been recommended in Behet's Disease
  4. Other Immunologic Agents
    1. Cyclosporine
    2. Intravenous Immunoglobulin (IVIg)
    3. Monoclonal Antibodies to cytokines, adhesion molecules, lymphocyte molecules
  5. Plasmapheresis
    1. Mainly effective for immune complex disease
    2. Also useful in hyperviscosity from cryoglobulinemia
    3. Less effective as single therapy in most vasculitides
  6. Topical nerve growth factor may improve ulcers due to certain vasculitides [14]
  7. Antiviral agents, including interferons, should be considered in virus-related disease [9]

References navigator

  1. Jennette JC, Falk RJ, Andrassy K, et al. 1994. Arthritis Rheum. 37(2):187 abstract
  2. Kathiresan S, Kelsey PB, Steere AC, et al. 2005. NEJM. 352(19):2003 (Case Record) abstract
  3. Rao JK, Allen NB, Pincus T. 1998. Ann Intern Med. 129(5):345 abstract
  4. Martinez-Taboada VM, Blanco R, Garcia-Fuentes M, Valverde V. 1997. Am J Med. 102(2):186 abstract
  5. Vallat JM, Cros DP, Hedley-Whyte ET. 2007. NEJM. 356(12):1252 (Case Record) abstract
  6. Watts RA, Carruthers DM, Scott DGI. 1995. Sem Arthritis Rheum. 25(1):28 abstract
  7. Ronthal M and Vonsattel JP. 1995. NEJM. 333(17):1135 (Case Record)
  8. Jacobson JO and De Leval L. 2001. NEJM. 345(19):1409 (Case Record)
  9. Guillevin L, Lhote F, Gherardi R. 1997. Curr Opin Rheumatol. 9(1):31 abstract
  10. Ledford DK. 1997. JAMA. 278(22):1962 abstract
  11. Woywodt A, Streiber F, de Groot K, et al. 2003. Lancet. 361(9353):206 abstract
  12. Bornke C, Heye N, Buttner T. 1999. Lancet. 353:1150 abstract
  13. Kevil CG and Bullard DC. 1999. Am J Med. 106(6):677 abstract
  14. Tuveri M, Generini S, Matucci-Cerinic M, Aloe L. 2000. Lancet. 356(9243):1739 abstract
  15. Kahn R, Herwald H, Muller-Esterl W, et al. 2002. Lancet. 360(9332):535 abstract
  16. Kay J and McCluskey RT. 2005. NEJM. 353(15):1605 (Case Record) abstract