4 Systemic vasculitis 1

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   Vasculitis is a nonspecific term that encompasses a large and heterogeneous
group of disorders that are characterized by inflammation of blood vessels. The term
"systemic necrotizing vasculitis" describes a systemic process in which blood vessel
architecture has been destroyed by inflammatory cells.

   As described by Mandell and Hoffman,1 vasculitis-induced injury to blood vessels
may lead to increased vascular permeability, vessel weakening that causes aneurysm
formation or hemorrhage, and intimal proliferation and thrombosis that result in
obstruction and local ischemia. Because systemic vasculitis can affect vessels of all
sizes and distributions, it has a wide spectrum of clinical features. Knowing the size
of the vessels affected in a particular patient is important, since vessel size carries
implications for the diagnosis, treatment and prognosis of the disease.

          It is critical to distinguish vasculitis occurring as a primary autoimmune
       disorder from vasculitis secondary to infection, drugs, malignancy or
       connective tissue disease such as systemic lupus erythematosus (SLE) or
       rheumatoid arthritis. Immunosuppressive therapy, which is sometimes used
       in the treatment of certain types of vasculitis, can have catastrophic
       consequences in the face of a systemic infection, as can delayed or
       inappropriate treatment of primary systemic vasculitis. Consequently, much
       of the diagnostic work-up in a patient with suspected vasculitis is directed at
       excluding secondary causes or conditions that can mimic vasculitis. When
       systemic vasculitis is suspected, the first step in the evaluation is to exclude
       other processes such as infection, thrombosis or neoplasia.

Classification of Vasculitis

   Vasculitis may be classified by the size and type of vessel involvement, by the
histopathologic features (leukocytoclastic, granulomatous vasculitis, etc.) or by the
pattern of clinical features.

   Identifying the type of vasculitis is important, since certain types may be self-
limited, whereas others may require corticosteroid therapy, with or without a
cytotoxic agent, or other modalities such as plasmapheresis. Initially in the work-up,
however, determining the extent of visceral organ involvement is more important
than identifying the type of vasculitis, so that organs at risk of damage are not
jeopardized if treatment is delayed or inadequate.
  The clinical features of primary vasculitis syndromes often overlap, and many
patients do not fit neatly into a well-defined type of vasculitis. These patients may be
described as having "undifferentiated systemic vasculitis." Such cases require close
follow-up, looking for signs of involvement in other organs or signs that may lead to
a specific diagnosis.

    Clinical Features and Primary Treatment of the Major Systemic Vasculitis

     Systemic vasculitis Common presenting
     syndrome            features                     Primary treatment

     Vasculitis of small
     Hypersensitivity    Palpable purpura             Often self-limited if
     vasculitis                                       offending agent is removed.
                                                      If isolated to skin, may not
                                                      require therapy. In more
                                                      severe cases, moderate- to
                                                      high-dose corticosteroid
                                                      therapy may be needed.
     Henoch-Schönlein Palpable purpura,               Often self-limited and
     purpura          arthritis,                      requires no treatment.
                      glomerulonephritis,             Steroid therapy for some
                      intestinal ischemia             cases of gastrointestinal or
                                                      renal involvement.
     Cryoglobulinemia Arthritis, Raynaud's            Corticosteroids;
                      phenomenon,                     plasmapheresis for severe
                      glomerulonephritis,             involvement. Antiviral
                      palpable purpura                therapy required if
                                                      associated with hepatitis C.
     Vasculitis of small
     and medium-sized
     Polyarteritis       Peripheral neuropathy,       High-dose corticosteroids,
     nodosa              mononeuritis multiplex,      often with cytotoxic agents
                         intestinal ischemia, renal   (e.g., cyclophosphamide
                         ischemia, testicular pain,   [Cytoxan])
                         livedo reticularis
     Microscopic         Pulmonary hemorrhage,        High-dose corticosteroids,
     polyangiitis        glomerulonephritis           often with cytotoxic agents
                                                      (e.g., cyclophosphamide)
     Churg-Strauss       Allergic rhinitis, asthma,   High-dose corticosteroids,
     vasculitis          eosinophilia, pulmonary      often with cytotoxic agents
                         infiltrates, coronary        (e.g., cyclophosphamide)
                         arteritis, intestinal
     Wegener's           Recurrent epistaxis or       High-dose corticosteroids
     granulomatosis      sinusitis, pulmonary         and cyclophosphamide.
                         infiltrates and/or           Corticosteroids and
                         nodules,                     methotrexate may be used
                         glomerulonephritis,          for less severe involvement.
                         ocular involvement
     Kawasaki disease    Fever, conjunctivitis,       High-dose aspirin and
                         lymphadenopathy,             intravenous immune
                         desquamating rash,           globulin
                         mucositis, arthritis,
                         coronary artery
     Vasculitis of large
     Giant cell, or       Headache, polymyalgia High-dose corticosteroids
     temporal, arteritis rheumatica, jaw or
                          tongue claudication,
                          scalp tenderness, fever,
                          vision disturbances
     Takayasu's arteritis Extremity claudication, High-dose corticosteroids
                          athralgias, constitutional
                          symptoms, renal

When to Suspect Systemic Vasculitis

  In particular, two types of presentation should alert the clinician to the possibility
of systemic vasculitis: unexplained ischemia, such as claudication, limb ischemia,
angina, transient ischemic attack, stroke, mesenteric ischemia and cutaneous
ischemia, particularly in a young patient or a patient without risk factors for
atherosclerosis and multiple organ dysfunction in a systemically ill patient, especially
in the presence of other suggestive clinical features.
    Clinical Features That Raise Suspicion of Vasculiti

    General clinical     Signs or presenting
    feature              disorder                     Type of vasculitis

    Constitutional    Fever, fatigue, malaise,     Any type of vasculitis
    symptoms          anorexia, weight loss
    Polymyalgia       Proximal muscle pain with Giant cell arteritis; less
    rheumatica        morning stiffness            commonly, other
    Nondestructive    Joint swelling, warmth,      Polyarteritis, Wegener's
    oligoarthritis    painful range of motion      granulomatosis, Churg-
                                                   Strauss vasculitis
    Skin lesions      Livedo reticularis, necrotic Polyarteritis, Churg-
                      lesions, ulcers, nodules,    Strauss vasculitis,
                      digital tip infarcts         Wegener's
                                                   hypersensitivity vasculitis
                      Palpable purpura             Any type of vasculitis
                                                   except giant cell arteritis
                                                   and Takayasu's arteritis
    Multiple          Injury to two or more        Polyarteritis, Churg-
    mononeuropathy separate peripheral nerves Strauss vasculitis,
    (mononeuritis     (e.g., patient presents with Wegener's
    multiplex)        both right foot drop and granulomatosis,
                      left wrist drop)             cryoglobulinemia
    Renal involvement Ischemic renal failure       Polyarteritis, Takayasu's
                      related to arteritis         arteritis; less commonly,
                                                   Churg-Strauss vasculitis
                                                   and Wegener's
                      Glomerulonephritis           Microscopic polyangiitis,
                                                   cryoglobulinemia, Churg-
                                                   Strauss vasculitis,Henoch-
                                                   Schönlein purpura

General Approach to Diagnosis
When systemic vasculitis is suspected, the diagnostic work-up can be approached in
a stepwise fashion:

   1. Attempt to exclude other processes, particularly infection, thrombosis and
          neoplasia, that can cause secondary vasculitis or can have features that
          mimic vasculitis. This must be done quickly to provide appropriate therapy
          for a potentially life-threatening condition. In addition, anti-inflammatory and
          immunosuppressive therapy of the systemic vasculitides is potentially toxic
          and may mask certain disorders, such as infection or a perforated viscus.

Conditions That Can Mimic Primary Systemic Vasculitis

Embolic disease                                         Thrombotic thrombocytopenic
Endocarditis                                            purpura
Atrial myxoma                                           Antiphospholipid antibody
Cholesterol embolization                                syndome
Vessel stenosis or "spasm"                              Heparin- or warfarin-induced
Atherosclerosis                                         thrombosis
Fibromuscular dysplasia                                 Systemic infection
Drug-induced vasospasm (e.g., ergots, cocaine,          Malignancy
phenylpropanolamine)                                    Other connective tissue
Intravascular lymphoma                                  disorders
Vessel thrombosis
Disseminated intravascular coagulopathy

   2. Consider the patient's age, sex and ethnic origin, since certain vasculitis
          syndromes occur more commonly in specific populations.

Demographic Associations of the Vasculitides

Age          Male-to-
group        female ratio   Ethnic origin      Type of vasculitis

Child        M=F            Any                Henoch-Schönlein purpura
             M>F            Asian > white >    Kawasaki disease
Young        M=F            Middle Eastern >   Behçet's disease
adult                       others
             F>M            Asian >> others    Takayasu's arteritis
Middle       M>F            Any                Wegener's granulomatosis, polyarteritis,
age                                            Churg-Strauss vasculitis
Elderly      F>M            Caucasian >>       Giant cell arteritis
 3. Determine which organs are involved and estimate the size of vessel
     involvement. The type and extent of organ involvement in vasculitis can be
     helpful in determining the specific type of vasculitis and the degree of
     urgency in initiating treatment. The clinical features in a given patient can be
     used to discern the size of the vessels affected by vasculitis. It should be
     recognized that the terms "small," "medium" and "large" to describe vessel
     size have different meanings for a pathologist, an angiographer and a

Clues for Identifying the type of Vessel Involvement in Vasculitis

                             Most likely affected Most commonly associated systemic
Clinical feature             vessel               vasculitis

Palpable purpura             Postcapillary venules Any type of vasculitis except giant
                                                   cell arteritis and Takayasu's arteritis
Skin ulcers                  Arterioles to small Polyarteritis, Churg-Strauss vasculitis,
                             arteries              Wegener's granulomatosis,
                                                   hypersensitivity vasculitis
Gangrene in an extremity     Small to medium-      Polyarteritis, Churg-Strauss vasculitis,
                             sized arteries        Wegener's granulomatosis
Gastrointestinal tract
Abdominal pain or            Small to medium-      Henoch-Schönlein purpura,
mesenteric ischemia          sized arteries        polyarteritis, Churg-Strauss vasculitis
Gastrointestinal bleeding    Capillaries to        Henoch-Schönlein purpura,
                             medium-sized          polyarteritis, Churg-Strauss vasculitis
Glomerulonephritis           Capillaries           Microscopic polyangiitis, Wegener's
                                                   granulomatosis, cryoglobulinemia,
                                                   Churg-Strauss vasculitis, Henoch-
                                                   Schönlein purpura
Ischemic renal failure       Small to medium-      Polyarteritis, Takayasu's arteritis; less
                             sized arteries        commonly, Churg-Strauss vasculitis
                                                   and Wegener's granulomatosis
Pulmonary hemorrhage         Capillaries; less     Microscopic polyangiitis, Wegener's
                             commonly small to     granulomatosis
  Pulmonary infiltrates or     Small to medium-      Churg-Strauss vasculitis, microscopic
  cavities                     sized arteries        polyangiitis
  Peripheral neuropathy        Small arteries      Polyarteritis, Churg-Strauss vasculitis,
                                                   Wegener's granulomatosis,
  Stroke                       Small, medium-sized Giant cell arteritis, SLE-associated
                               or large arteries   vasculitis

   4. Attempt to distinguish the specific type of vasculitis on the basis of the above
       information and the pattern of the clinical features.

   Laboratory Testing

      Although occasionally helpful in classifying vasculitis, laboratory testing is
   most important in determining organ involvement and excluding the presence of
   other diseases. Important routine tests include complete blood cell count,
   urinalysis, blood urea nitrogen, creatinine and liver enzyme levels. Leukocytosis,
   anemia of chronic disease, a high erythrocyte sedimentation rate (ESR) and an
   elevated C-reactive protein level are commonly found in most types of vasculitis.
   Although ESR is almost always elevated in vasculitis, a normal ESR does not rule
   out systemic vasculitis.1 If the patient has renal failure or proteinuria and
   hematuria on urinalysis, a fresh-spun urine sample should be evaluated for red
   blood cell casts or dysmorphic red cells that would suggest the presence of a

Laboratory Tests to Consider in the Evaluation of Systemic Vasculitis

Laboratory test                     Purpose or interpretation

Routine tests (including complete   Evaluate for hematologic, renal and other organ
blood cell count, liver enzymes,    involvement
creatinine, urinalysis)
Blood cultures                      Rule out infection
Erythrocyte sedimentation rate      High value suggests inflammatory disease
C-reactive protein                  High value suggests inflammatory disease
Rheumatoid factor                   Very high titers in rheumatoid arthritis,
                                      Sjögren's syndrome and cryoglobulinemia-
                                      associated vasculitis
Antinuclear antibody                  Screen for SLE and Sjögren's syndrome
Complements (C3, C4, CH50)            Low complement levels suggest consumption by
                                      immune complexes, which are commonly found
                                      in SLE and cryoglobulinemia
Cryoglobulins                         Must be present to diagnose mixed essential
                                      cryoglobulinemia but can be found in any
                                      primary or secondary vasculitis
ANCA                                  Cytoplasmic ANCA pattern specific for
                                      Wegener's granulomatosis; perinuclear ANCA
                                      pattern may occur in other vasculitides
Creatine phosphokinase                Elevation suggests myositis, which can occur in
                                      many vasculitis syndromes
RPR/VDRL                              Rule out syphilis
Serum protein electrophoresis         Evaluate for plasma cell dyscrasias
Hepatitis B and C serology            Rule out hepatitis B or hepatitis C infection
HIV                                   Rule out HIV infection
Anti-glomerular basement              Rule out Goodpasture's syndrome, which can
membrane                              mimic vasculitis and cause pulmonary
                                      hemorrhage and glomerulonephritis

SLE = systemic lupus erythematosus; ANCA = anti-neutrophil cytoplasmic antibodies; RPR =
rapid plasmin reagin; HIV = human immunodeficiency virus.

   Chest radiographs may reveal asymptomatic pulmonary involvement. If findings
suggestive of peripheral neuropathy or muscle inflammation are noted on the
history and physical examination, nerve conduction velocity and electromyographic
testing can help confirm these suspicions and serve as a guide for biopsy.

   Although rheumatoid factor can be present in any inflammatory disease, it is
more often found in rheumatoid arthritisassociated vasculitis, Sjögren's syndrome
and mixed cryoglobulinemia. Hepatitis B, hepatitis C and human immunodeficiency
virus (HIV) serologies should be obtained, since these infections are sometimes
associated with vasculitis.8-10 While complement levels (C3, C4 and CH50) are often
normal or high in other types of vasculitis, they tend to be low in SLE-associated
vasculitis, cryoglobulinemia and hepatitis B and Cassociated vasculitis, reflecting
consumption by circulating immune complexes.
   Cryoglobulins can be present in malignancy (plasma cell dyscrasias, lymphoma
and leukemia), chronic infections (hepatitis B, hepatitis C and endocarditis),
inflammatory rheumatic disease (Sjögren's syndrome, SLE and rheumatoid arthritis)
or in the syndrome of mixed essential cryoglobulinemia. Mixed essential
cryoglobulinemia is now known to be strongly associated with hepatitis C.
Cryoglobulins are antibodies that reversibly precipitate in cold. They should be
collected in a warmed tube and kept warm on transport to the laboratory.

   There are two staining patterns for anti-neutrophil cytoplasmic antibodies
(ANCA). Cytoplasmic ANCA (C-ANCA) most often represents antibody to proteinase 3
and is present in up to 90 percent of patients with active, diffuse Wegener's
granulomatosis and quite specific in the appropriate clinical setting. Perinuclear
ANCA (P-ANCA), which is often caused by anti-myeloperoxidase antibody, is less
specific but is often present when vasculitis affects small to medium-sized arteries.

Arteriography and Biopsy

  Confirmation of a clinical suspicion of vasculitis usually requires arteriography,
biopsy, or both. Evaluation should be directed toward establishing a tissue diagnosis,
if possible. In general, because "blind" biopsy of asymptomatic sites or organs
generally has a low yield,2 it is best to "go where the money is." For example, if a
patient is over age 50 and presents with a new, unexplained headache and elevated
ESR, with or without a tender or abnormal temporal artery, a temporal artery biopsy
would be indicated. Similarly, in a patient who presents with a multisystem illness
and testicular pain and swelling, a testicular biopsy should be considered. Sural
nerve biopsy may be indicated in a patient with numbness and tingling in a lower
extremity. If the urine sediment is abnormal, a renal biopsy might be obtained.

  If a biopsy is impractical, an angiogram may be diagnostic. An angiogram should
be obtained in cases of suspected large-vessel vasculitis, such as of the branches of
the aorta, which may be manifested as extremity ischemia or claudication. A patient
with abdominal pain may have mesenteric or renal vasculitis. If visceral involvement
is suspected (and in the absence of a surgical abdomen), a visceral angiogram to
include the celiac, mesenteric, renal and, perhaps, hepatic arteries should be

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