I. Definitions and pathophysiology

  1. Inflammation in blood vessel walls, leading to
  1. Tissue ischemia and necrosis
  2. Aneurysms and rupture
  1. Can occur in any blood vessel
  2. Tends to be irregular and segmental
  3. May be focal or diffuse, acute or chronic
  4. In some forms, associated with immunoglobulin deposition, which presumably leads to complement activation and PMN recruitment
  5. All vasculitides can present with palpable purpura, often on the lower extremities
  6. Mechanisms of inflammation may vary in different forms of vasculitis
  7. Infection, including hep B and C may play a role in some vasculitis syndromes
  8. Neoplasms, e.g. lymphomas and hairy cell leukemia may also be associated

II. Large artery vasculitides

  1. Takayasu's arteritis
  1. Pathophysiology
  1. Involves the aorta (us. the most severely affected vessel) and its primary branches, including renal and mesenteric aa.
  2. Continuous or patchy granulomatous inflammation with lymphocytes, histiocytes, and multinucleated giant cells
  3. Can produce either luminal compromise (more common) or dilatation and aneurysms
  1. Us. young women, most often Asian or European background, us. onset age 10-30y
  2. Initial presentation includes fever, arthralgias, arthritis, and malaise; also headache, dizziness
  3. Other manifestations are often chronic:
  1. Lower-extremity or mesenteric claudication
  2. Aortic insufficiency from dilatation of aortic root
  3. Coronary insufficiency from narrowing of ostea of coronary aa.
  4. Renal aa. stenosis may cause HTN
  1. Px may show asymmetric BP, diminished and/or asymmetric peripheral pulses and bruits over large proximal aa.
  2. Seldom causes cutaneous manifestations
  3. Elevated ESR and platelet count during active disease
  4. Moderate anemia us. present
  5. Treatment with corticosteroids suppress the sx and us. halt progression; methotrexate has been used in combination
  6. Vascular bypass may be effective in cases of severe luminal compromise; angioplasty not as effective
  1. Giant cell ("Temporal") arteritis
  1. Pathophysiology
    1. A chronic, granulomatous vasculitis involving medium-to-large-sized arteries, particularly the cranial arteries including the superficial temporal artery
    2. Histology similar to Takayasu's with histiocytes, lymphocytes, and multinucleated giant cells (though the latter present in only 50% of cases)
    3. End result is luminal occlusion and tissue ischemia
  2. Usual onset is > 50yo; peak incidence is at > 70yo
  3. Female:male
  4. 50% of patients with giant cell arteritis also have Polymyalgia Rheumatica
  5. Clinical and laboratory features
    1. Gradual-onset constitutional symptoms, including fatigue, malaise, low-grade fever, anorexia with weight loss, and myalgias
    2. Findings related to end-organ ischemia, including headache, jaw or arm claudication, diplopia, amaurosis fugax, scalp tenderness (particularly over temporal artery), and "aortic arch syndrome."
      1. Visual loss may occur & may be permanent
    3. Fundoscopic features
      1. Swollen disc; some hemorrhage, no plethora
      2. Central retinal a. occlusion causes "box-carring"
    4. Can also involve aorta cause thoracic aortic aneurysm; us. a late complication (years after dx); therefore, yearly CXR may be appropriate
    5. ESR us. markedly elevated (though can be nl in 10-20% of pts with active disease)
    6. Thrombocytosis is more sensitive than ESR elevation
    7. Can have moderate normochromic normocytic anemia
    8. Mild elevation of transaminases occurs in 25-30% of cases.
  6. Diagnosis
    1. Temporal artery tenderness can add to suspicion but is not diagnostic
    2. Temporal artery biopsy is gold standard (ok if done < 5d after start of steroid Tx)
      1. Need at least 2cm for diagnosis
      2. Bilateral biopsies can increase the diagnostic yield, since sensitivity of unilateral biopsy is only 87% (J. Rheumatol. 36:794, 2009-JW)
    3. Duplex ultrasonography may reveal characteristic finding of "halo" sign-95% specific but not highly sensitive (NEJM 337:1336, 1997--JW)
    4. American College of Rheumatology Diagnostic Criteria (from Rhem. Dis. Clin. N. Am. 16:399, 1990, cited in an AFP article)-3 or more of:
      1. >50yo
      2. New-onset localized HA
      3. Temporal aa. tenderness or pulse reduction
      4. ESR 50 mm/h or greater (by Westergren method)
      5. Abnormal result on temporal artery biopsy
  7. Treatment
    1. Prednisone 40-60mg/d
  1. Start immediately upon likely diagnosis (do not wait for biopsy)
  2. Continue till normalization of clinical and lab features (usually 2-6wks
  3. Taper gradually over months to 2-3y (e.g. taper prednisone 2.5-5mg/d Q2wks until ESR goes up or sx return, then back up 1 for chronic dose)
  4. Symptoms usually improve within 72h after initiation
  5. If relapse occurs, resume steroid therapy at previously effective dose
    1. High dose induction of steroid therapy to limit duration of treatment:
      1. In a study in 27 pts with biopsy-proven giant-cell arteritis randomized to methylprednisolone 15mg/kg/d x 3d vs. placebo; all pts recevied prednisone 40mg/d to start and gradually tapered according to a fixed protocol by ESR and CRP levels, the % of pts who at 36wks was taking < 6mg/d of prednisone was sig. higher in the methylprednisolone group (71% vs. 15%); diff. also sig. at 78wks (Arth. Rheum. 54:3310, 2006--JW)
    2. Methotrexate: In a randomized trial in 42 adults with bx-proven temporal arteritis randomized to methotrexate 10mg Qwk vs. placebo x 2y (all pts also received pred. x 6mos tapering from 60mg/d); methotrexate group had sig. lower risk of recurrent sx (45% vs. 84%) and lower mean cumulative dose of prednisone (4.2g vs. 5.4g) (Ann. Int. Med. 134:106, 2001--JW)
    3. Dapsone and cytotoxic drugs have been used though little data from controlled trials
    4. Low-dose aspirin may reduce ischemic complications; If use steroids + aspirin should consider proton-pump inhibitor for GI protection
    1. Polymyalgia Rheumatica
    2. Kawasaki Disease

    III. Vasculitides affecting mid-sized and small arteries

    1. Polyarteritis nodosa
    1. Acute necrotizing vasculitis of medium-sized and small muscular arteries throughout the body (particularly skin, muscle, bone, nerves, heart, gut, and renal arteries)
    2. Male : Female 2:1; us. occurs in mid-40's and 50's (though pediatric cases have been reported; see J. Ped. 145:517, 2004) and in all racial groups
    3. Classically presents with fever and some combination of fatigue, weight loss, myalgias, arthralgias, mononeuritis multiplex, skin ulcers, livedo reticularis, renal disease, hypertension, and mesenteric ischemia
    4. Can cause death from GI ischemia and renal insufficiency early on; infection and cardiovascular complications later on
    5. 5y survival rate 60-80%
    6. Probably many causes; hep B and hep C account for some cases
    7. Dx: bx of affected tissues, mesenteric arteriography if abd. sx are present; can be associated with presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
    8. Tx with corticosteroids; can be combined with cyclophosphamide in severe cases
    1. Wegener's granulomatosis
    1. Peak incidence in 30's and 40's; slight male predominance
    2. Typically causes focal granulomatous inflammation and vasculitis in smaller vessels of upper & lower resp. tracts and necrotizing glomerulonephritis; may, however, involve any organ system, including CNS
    3. Presentation: Epistaxis, nasal pain, nasal crusting, unresolving sinusitis, venous thrombosis
    4. May be rapidly fatal or more chronic
    5. Dx is by clinical features, CXR, and histopathology
    6. Laboratory diagnosis
      1. ANCA is useful in initial dx and following progression, esp. "cytoplasmic" ANCA (c-ANCA), which is highly specific and sensitive for active Wegener's
      2. Perinuclear ANCA (p-ANCA) is more closely associated with microscopic polyangiitis, a smaller-vessel vasculitis
    7. Tx: cyclophosphamide + prednisone highly effective at achieving remission. Taper prednisone; continue cyclophosphamide x 1y. Methotrexate has been used as an alternative to cyclophosphamide
    1. Microscopic polyangiitis
      1. Shares some features with Wegener granulomatosis but involves skin in about 50% of patiens
      2. Can also affect kidneys (~80%), lungs (~20%), joints (~70%), GI tract (~40%), and peripheral nerves (~20%).
      3. Can be (rarely) associated with Churg-Strauss syndrome which can cause asthma, fever, and eosinophilia (absolute eosinophil count >1500).
      4. Labs: Serum myeloperoxidase-anticytoplasmic antibody (p-ANCA)

    2. Thromboangiitis Obliterans (Buerger's Disease)
      1. A vasculitis of small and medium-sized arteris and veins of the extremities, usually resulting in formation of an occlusive intravascular thrombus
      2. No specific diagnostic test; Acute-phase reactants, including CRP and ESR, are normal
      3. Smoking is a strong risk factor
      4. Onset usually in the 5th decade of life; men > women
      5. Often presents with claudication, then ischemic pain at rest and ulcerations of toes or fingers
      6. Tends to spread from distal to proximal over time
      7. Tx = smoking cessation; prostaglandin analogues have been studied.

    IV. Vasculitis in rheumatic diseases

    1. Rheumatoid Arthritis: can get lymphocytic vasculitis in synovial tissues; can lead to skin infarctions
    2. Ditto for scleroderma
    3. Can get necrotizing vasculitis in severe RA or other connective tissue disease; histopathology common to many diseases

    V. Small vessel vasculitides

    1. AKA "hypersensitivity vasculitis," "leukocytoclastic vasculitis" though the latter describes a histopathology common to many diseases
    2. Can occur with many diseases, including Henoch-Schonlein purpura, microscopic polyangiitis, mixed cryoglobulinemia, hypocomplementemic urticarial vasculitis; also cutaneous vasculitides associated with biliary cirrhosis, UC, Ca, and other diseases.

    VI. Approach to pt with vasculitis

    1. Hx: emphasize exposure to drugs, infectious hepatitis, coexisting illness
    2. Bx of affected tissues
    3. Labs: ANA, complement for cryoglobulinemia or connective tissue disorders, C-ANCA for Wegener's, u/a and Cr to detect renal involvement
    4. Arteriography for medium-sized and large-vessel arteritides

    VII. Management (see also sections on individual disorders)

    1. For drug-related, discontinue offending drug
    2. Observation OK if vasculitis confined to skin, e.g. in mild Henoch-Schonlein purpura.
    3. For broader involvement, medication management is often used
      1. Corticosteroids
      2. Cytotoxic drugs if rapidly progressive or if renal or abdominal vessels involved
      3. Rituximab (a chimeric antibody that targets CD20+ B cells) has had some success in early studies for pts with ANCA-associated vasculitis
    4. IgG may be helpful for Kawasaki's
    5. For prolonged cutaneous vasculitis not ass'd with recognizable causes, NSAIDs, colchicine, antihistamines and dapsone have been used
    6. Taper meds to lowest effective dose but expect recurrences
    7. Consider monitoring ESR though keep in mind its lack of specificity

    (Sources include Core Content Review of Family Medicine: Hunder, G. Vasculitis: Diagnosis and Therapy. Am. J. Med 100(2A): 37S-45S, 1996)