Hypersensitivity vasculitis (leukocytoclastic vasculitis, or LCV) is a histopathologic term commonly used to denote a small-vessel vasculitis. Many possible causes exist for this condition, but a cause is not found in as many as 50% of patients.
Hypersensitivity vasculitis (leukocytoclastic vasculitis) may be localized to the skin, or it may manifest in other organs. The internal organs most commonly affected are the gastrointestinal tract and the kidneys. Joints are also commonly affected. The prognosis is good when no internal involvement is present. The disorder may be acute or chronic.
Epidemiology and pathophysiology
Hypersensitivity vasculitis is the most common vasculitic syndrome encountered in the clinical practice of allergy and immunology. Hypersensitivity vasculitis is comprised of a broad group of diseases which share a histological pattern of post-capillary venulitis with leukocytoclastic vasculitis (Leukocytoclasis refers to the nuclear debris remaining after neutrophils fragment as they infiltrate the affected blood vessel.)
In the past, circulating immune complexes were believed to cause hypersensitivity vasculitis (leukocytoclastic vasculitis).Although immune complexes are involved in the pathogenesis of hypersensitivity vasculitis (leukocytoclastic vasculitis), other autoantibodies cause disease manifestations, such as antineutrophil cytoplasmic antibody (ANCA), other inflammatory mediators, and local factors that involve the endothelial cells and other adhesion molecules. The exact mechanisms remain to be elucidated.
Figure 2. Hypersensitivity Vasculitis
This figure shows a low power view of hemotoxylin and eosin stained skin biopsy in a subject with hypersensitivity vasculitis. The biopsy demonstrates leukocytoclastic vasculitis. The black arrows point to small blood vessels in the subcutaneous tissue with perivascular leukocytes. A high power view would show blood cell extravasation and nuclear debris from lysed white blood cells (nuclear dust).
These diseases tend to affect the skin and occasionally the kidney. Neutrophil fragmentation is associated with inflammation resulting in extravasation of red blood cells. Together these features distinguish hypersensitivity vasculitis from urticaria.
Red cell extravasation is responsible for the purpuric appearance of hypersensitivity vasculitis. Low-pressure, post-capillary venules cause a predilection for vessel involvement at sites of increased hydrostatic pressures. Hydrostatic pressures are greatest in dependent portions of the body—the distal legs in individuals who are upright and the sacral area in bedridden subjects. This distribution of cutaneous involvement is highly suggestive of hypersensitivity vasculitis.
The majority of hypersensitivity vasculitis is secondary to another, primary disorder. These secondary syndromes include drug hypersensitivity, for example penicillin allergy with serum sickness; autoimmune diseases such as systemic lupus erythematosus; and chronic hepatitis with cryoglobulinemia and malignancy.
The hallmark of the cutaneous reaction associated with hypersensitivity vasculitis is palpable purpura. Other cutaneous manifestations include a macular or papular rash, vesicles, bullae, subcutaneous nodules, ulcers, and urticaria. Skin lesions may be pruritic but more often are slightly painful or produce a burning sensation. Edema may accompany the lesions, and hyperpigmentation results from the hemosiderin presence caused by extravasation of red blood cells.
Currently there is no definitive laboratory diagnosis of hypersensitivity vasculitis other than a skin biopsy demonstrating leukocytoclastic vasculitis (Figure 2). Positive immunofluorescence for immunoglobulin and complement may be seen but is not required for diagnosis. Mild leukocytosis—with or without eosinophilia—and increased acute-phase indicators, such as erythrocyte sedimentation rate (ESR) or C-reactive protein, are typical but non-specific in hypersensitivity vasculitis. Laboratory tests and physical examination should focus on evaluating underlying diseases we know to be associated with this syndrome.
- Patients with vasculitis of their skin may report itching, a burning sensation, or pain, or they may have asymptomatic lesions.
- Vasculitis of the skin may occur in the absence of any systemic disease.
- Vasculitis may manifest as an eruption only, or it may occur in conjunction with collagen vascular disorders, paraproteinemia, ingestants (drugs or foods), infections, or malignancy (rare).8,9,10,11
- Elicit information about possible systemic manifestations from patients. Inquire about the presence or the absence of fever, arthralgia, arthritis, myalgia, abdominal pain, diarrhea, hematochezia, cough, hemoptysis, sinusitis, paresthesia, weakness, and hematuria.
- Obtain information about symptoms of an associated disorder. Determine the patient’s history of intravenous drug use, hepatitis, transfusion, and travel, along with symptoms or a history of inflammatory bowel disease and collagen-vascular disorder, particularly rheumatoid arthritis, lupus erythematosus, or Sjögren syndrome.
Palpable purpura is the most common manifestation of cutaneous vasculitis, but other manifestations may occur.
- Palpable purpura is the most frequent presentation of small-vessel vasculitis.
- Lesions are usually round and 1-3 mm in diameter.
- Lesions may coalesce to form plaques; they may ulcerate in some instances.
- Retiform lesions were associated with immunoglobulin A (IgA)–related immune complex disease in one study; however, this result has not been validated in subsequent studies.
- Palpable purpura is most frequently observed on the legs, but any surface can be involved. Purpuric lesions are sometimes barely palpable.
- Urticarial lesions may occur in some patients; rarely, this type of lesion can predate purpuric lesions.
- Urticarial lesions are of a different character than routine urticaria, tending to be of longer duration (often >24 h) and tending to resolve with some residual pigmentation or ecchymosis. Patients complain of a burning sensation rather than itching.
- To determine the duration of individual lesions, encircle several lesions and ask the patient to observe them periodically and note when they resolve or when they change shape and when a lesion is outside the encircled area.
- Patients with hypocomplementemic urticarial vasculitis may develop chronic obstructive pulmonary disease; carefully examine the heart and the lungs.
- Livedo reticularis is a rare manifestation of small-vessel vasculitis. It is more frequent in patients with occlusive or inflammatory disease of medium-sized vessels.
- Nodular lesions may occur in some patients with small-vessel vasculitis.
- Ulceration is more common in vasculitis that affects larger vessels, but it may complicate intense purpura.
- Perform a careful physical examination in patients with vasculitis, including specific observation of cardiopulmonary, musculoskeletal, and gastrointestinal systems.
- Between one third and one half of cutaneous vasculitis cases are idiopathic; the remainder have a variety of causes.
- Antibiotics are the most common drugs that can cause cutaneous vasculitis, particularly beta-lactams. Nonsteroidal anti-inflammatory drugs and diuretics also frequently cause vasculitis. However, almost all drugs are potential causes.
- Various infections may be associated with vasculitis. Upper respiratory tract infections (particularly beta-hemolytic streptococcal infection) and viral hepatitis, particularly hepatitis C, are most often implicated. HIV infection may also be associated with some cases of cutaneous vasculitis. Ascertaining whether a drug (eg, antibiotic) or an infection (eg, upper respiratory infection) is responsible for the disease is impossible because the occurrence of vasculitis postdates infection and the drug used to treat the infection.
- Foods or food additives may cause vasculitis.
- Hepatitis C is a regularly recognized cause of vasculitis, probably through the presence of cryoglobulins. However, of 1614 patients with hepatitis C, vasculitis occurred in only 12 patients (9 with cryoglobulinemia, 3 without). Interestingly, cryoglobulins were present in roughly 40% of those tested; many patients with cryoglobulins (98%) did not have vasculitis despite an abnormal circulating paraprotein. Hepatitis B was implicated in some cases of vasculitis in the past.
- Collagen vascular diseases account for 10-15% of cases of vasculitis.
- In particular, rheumatoid arthritis, Sjögren syndrome, and lupus erythematosus may have an associated vasculitis.
- The presence of vasculitis often denotes active disease and possibly a poorer prognosis.
- Inflammatory bowel disease, ulcerative colitis, or Crohn colitis may be associated with cutaneous vasculitis.
- Malignancy accounts for less than 1% of cases of cutaneous vasculitis.
- Perhaps lymphoproliferative diseases are more common (particularly hairy cell leukemia); however, any type of tumor at any site may possibly be related to cutaneous vasculitis.
- Effective tumor therapy in some patients has led to resolution of the vasculitis.
- Small-vessel cutaneous vasculitis may be seen uncommonly in patients with a larger vessel vasculitis, such as Wegener granulomatosis, polyarteritis nodosa, or Churg-Strauss syndrome.
Treatment for hypersensitivity vasculitis should follow a protocol for relatively benign prognosis if no renal involvement is found. The syndrome is frequently limited to the skin and usually does not lead to life-threatening complications. If a specific antigen is detected, treatment should be targeted at eliminating any responsible infection or terminating administration of any identified causal drug. Antihistamine therapy for pruritus, treatment with nonsteroidal anti-inflammatory drugs for painful lesions, and—rarely, but with caution—short courses of systemic glucocorticoids may prove useful.
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