LabMed

Hypersensitivity Vasculitis

At a Glance

Hypersensitivity ('allergic’) vasculitis, which is less used now, is a generic term for small vessel cutaneous vasculitis affecting capillaries, venules, or arterioles. It includes mainly cutaneous leukocytoclastic angiitis and cryoglobulinemic vasculitis. Immune complex-mediated damage of the vessel wall is the main pathogenic factor. However, additional pathogenic factors may be present and can contribute to the symptoms. Patients with microscopic polyangiitis which connotes pauci-immune (i.e., few or no immune complex deposits) are excluded from this definition.

Hypersensitivity vasculitis may be secondary to a) bacterial infections (streptococci, bacterial endocortitis), spirochetes, reckettsia, viral infections (Hepatitis C, less commonly in other viral infections such as EBV) with and without cryoglobulinemia; b) drugs (penicillin, sulphonamides, thiazides); c) serum sickness (induced by biological products such as Thymoglobulin); d) autoimmune diseases (SLE, Sjogren's syndrome); e) malignancies (lymphoma).

Typical features may include palpable purpura, skin ulcerations and systemic features (fever, arthralgia, myalgia). Systemic vascular involvement depends on the etiology and may include the kidneys (glomerulonephritis), gastrointestinal track, or a peripheral neuropathy. Careful past medical history may reveal past illness (upper respiratory tract infection), drug intake, vaccinations or chemical and food allergies.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The most useful laboratory tests to confirm the clinical diagnosis include: Complement C3 and C4, Cryoglobulins, Rheumatoid factors, and ESR (Table 1). In addition, antistreptolysin O antibody titers, antinuclear antibodies (ANA, anti-dsDNA, anti-Sm/RNP, anti-SSA/SSB), and urinalysis can be used to identify the cause of the vasculitis. Immunoglobulin measurement contributes very little to the diagnosis.

Exclusion tests may include anti-neutrophil cytoplasmic antibodies (ANCA, including anti-MPO and anti-PR3) which are specific for ANCA-associated vasculitides (Wegener's granulomatosis, Microscopic polyangiitis, Churg-Strauss syndrome).

Follow up tests should include Complement C3 and C4, and cryoglobulin levels to assess response to treatments; the persistance of hypocomplementemia usually correlates with levels of circulating immune complexes.

Other useful tests for monitoring include ESR; urianalyis and serum creatinine in case of kidney involvement. (Table 1)

Measurement of cryoglobulins can be assessed visually ("cryocrit") or by a more accurate quantitation using turbidimetric analysis. The precipitate can then be analyzed to determine the isotype of the immunoglobulins using protein electropheresis.

Table 1

Test Results Indicative of the Disorder
C3 and C4 Cryoglobulins Skin Biopsy
Usually decreased Mixed Cryoglobulins may be present with a Rheumatoid factor activity Leukocytoclastic vasculitis

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

The interpretation of serum levels of C3 and C4 in patients with rheumatic diseases can be difficult because these components are greatly increased in plasma in response to inflammation.

In addition, a significant number of healthy individuals have a congenital deficiency of C4 (C4 null allele) resulting in a lower level of C4 production. Since the C4 reference range represents the normal population as a whole, for some individuals, this reference range may be misleading.

Congenital complement C1q, C2 or C4 deficiencies are associated with increased risk of vasculitis.

Low serum complement levels can be observed due to an artifact if tests are not performed on fresh sera or sera that are not stored at low temperature.

Measurement of Cryoglobulin levels must be performed on blood drawn into a warm tube and transported to the lab at 37oC; this is important, as cryoglobulins may be lost if the blood temperature decreases before a clot is formed. Blood clot must be formed at 37oC for 1-2 hours and spun at 37oC. Serum should be incubated for a few days at low temperature (4oC).

What Lab Results Are Absolutely Confirmatory?

C3 and C4 levels are the very useful tests to confirm the diagnosis of acquired hypocomplementemia, seen in patients with immune complex-mediated vasculitis. However, the most important diagnostic test is a skin biopsy and a biopsy of an affected organ such as the kidneys.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The presence of IgA-dominant immune deposits affecting capillaries, venules or arteries should raise a strong suspicion for Henoch-Shonlein purpura (HSP). HSP occurs more often in children than in adults (80% versus 10-20%). In adults complications are more severe.

In case of urticarial lesions with hypocomplementemia (hypocomplementemic urticarial vasculitis), testing for anti-C1q antibodies should be requested.

Since congenital complement C1q, C2 or C4 deficiencies are associated with increased risk of vasculitis, if there is a clinical suspicion for a congenital C1q, C2 or C4 deficiency, confirmatory testing can be done using a CH50 assay plus measurement of a specific complement component.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Atypical P-ANCA can be seen in patients with drug-induced vasculitis or in autoimmune diseases such as SLE. However, these P-ANCA are usually against elastase or lactoferrin and not against MPO or PR3, which are associated with Wegener's granulomatosis and microscopic polyangiitis. Since most forms of vasculitis can affect the skin it is important to identify those with underlying severe systemic disease such as ANCA-associated vasculitis or PAN in order to initiate appropriate treatments.

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