Hypersensitivity Vasculitis and Allergy Vasculitis
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
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.
Diagnosis 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).
- 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 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.
Allergic vasculitis is hypersensitivity to a drug or foreign substance that leads to inflammation and damage to blood vessels of the skin. Alternative Names Vasculitis – allergic hypersensitivity; Cutaneous leukocytoclastic vasculitis. Allergic vasculitis is caused by an allergic reaction to a drug or other foreign substance.
- Skin lesions usually located on legs, buttocks, or trunk
- Blisters on the skin
- Urticaria (hives), may last longer than 24
Pauci-immune vasculitis is appreciated For a while it was considered that possibly most, maybe even all, small-vessel vasculitides were caused by immune complex deposition or anti-basement membrane antibodies. And, of course, when you look at the glomerular involvement, which is frequent in patients with small-vessel vasculitis, you certainly do see some patients with granular staining indicative of an immune complex disease and linear staining indicative of anti-basement membrane disease. However, it became apparent to any number of investigators that the involved vessels other than glomeruli as well as the glomeruli in many patients with small-vessel vasculitis, especially patients with Wegener’s granulomatosis and microscopic polyangiitis, did not have staining for immunoglobulin or complement. So this paucity of staining was somewhat of a problem in explaining the pathogenesis.
Prevalence of immune complexes in vasculitis
And in fact, these patients with pauci-immune vasculitis were quite common. For example, in this analysis of patients evaluated in my laboratory, you can see that the pauci-immune category is about equal to the immune complex category and much more frequent that anti-GBM disease if you look at all patients with inflammatory glomerulonephritis. And as you look at more and more severe glomerulonephritis, the frequency of this pauci-immune category goes up even more. So if you look at those patients who have greater than 50 percent of their glomeruli involved with crescents, this pauci-immune category is the most common. And, in fact, if you look at those few patients in whom you see necrotizing vasculitis in addition to glomerulonephritis in the kidney, there is a strong predilection here for the pauci-immune category.
Pauci-immune glomerulonephritis and ANCA positivity
Also in older patients, as has been seen here in Scandinavia by Pedersen and her associates in Stockholm, the frequency of this pauci-immune pattern and in fact this ANCA-associated disease pattern goes up. You can see here in this particular cohort, 90 percent of the patients were ANCA positive. So the pauci-immune category of glomerulonephritis and small-vessel vasculitis almost equates with ANCA vasculitis and glomerulonephritis.
As will be discussed later in detail by Jörgen Wieslander, ANCA specificity, as is well known to this group, in patients with glomerulonephritis vasculitis breaks down primarily into patients with anti-proteinase 3 specific antibodies that react with the cytoplasm and cause the C ANCA staining pattern and anti-myeloproxidase specific autoantibodies that react with antigen that is redistributed to the nucleus artifactually during preparation of the substrate if you use alcohol-fixed neutrophils. So these two ANCA specificities then mark a subset of small-vessel vasculitis that probably have a related pathogenesis.
ANCA vasculitis: glomerular and extrarenal involvement patterns If you look at all patients with ANCA- positive glomerulonephritis, some of them apparently have involvement of no other tissues from all of the evidence that you can collect. But most patients with ANCA-positive glomerulonephritis have evidence for involvement of other viscera. The diagnostic challenge in these patients is to categorize those patients into some specific set if possible. This may be a somewhat academic exercise because, as we will discuss some later, the treatment may be very similar if not identical for all of these categories. So the main step is initially realizing that it is an ANCA-positive necrotizing small-vessel vasculitis and possibly proceeding with treatment at that point and trying to categorize them further. If there is no systemic involvement, just ANCA glomerulonephritis, some prefer the term renal-limited vasculitis. If there is involvement of the respiratory tract or elsewhere with granulomatous inflammation, then Wegener’s granulomatosis is the proper designation if there is no history of asthma. If there is a history of asthma, then Churg-Strauss syndrome. In these patients, the eosinophilia is usually more than 10 percent. If there is no evidence for Wegener’s granulomatosis or Churg-Strauss syndrome, then the term that I would suggest is microscopic polyangiitis. I believe this is preferable to microscopic polyarteritis because many of these patients have no apparent involvement of arteries at all. They may have pulmonary capillaritis, they may have postcapillary venulitis in the skin, they may have glomerulonephritis, but they may not have arteritis. So the term microscopic polyangiitis is a better generic term.
With respect to the association of the autoantibody specificities, various cohorts have been analyzed. This is an analysis of 111 patients from our cohort of ANCA-diseased patients. There is a predominance of the anti-PR3 specificity in patients with the Wegener’s granulomatosis phenotype, but at least in our experience at this point, about one-third of these patients have anti-MPO specificity. In the microscopic polyangiitis patients, there is about an equal frequency of anti-MPO and anti-PR3 antibodies with possibly a little bit of predominance of anti-MPO specificity. In the patients with renal-limited disease, there is a very striking predilection for the anti-MPO.
Chapel Hill nomenclature system The categorization of small-vessel vasculitis in patients with renal disease can usually be accommodated by what is sometimes referred to as the Chapel Hill nomenclature system, which categorizes some of these major forms of small-vessel vasculitis as Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, all associated with ANCA; Henoch-Schönlein purpura, with IgA dominant immune complexes; cryoglobulinemic vasculitis, with circulating cryoglobulins and cryoglobulins in the tissues; and then occasional patients who have small-vessel vasculitis just confined to the skin. These patients may have a self-limited, benign course, but some of these patients will ultimately be found to have systemic involvement including the kidney.
Vasculitides not on the above list Of course, there are other forms of small-vessel vasculitis not accommodated in this particular list that I’ve described earlier: lupus- associated vasculitis, some forms of drug-induced vasculitis, infection-associated vasculitis. But in all of these circumstances, I think the initial approach should be to recognize that your patient has a small-vessel vasculitis and then as best you can to pursue additional diagnostic procedures, for example immunohistology on biopsy tissue, serology, to put them into a more specific category because that will impact substantially on the appropriate treatment regimen.
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