Hypersensitivity vasculitis, which is usually represented histopathologically as leukocytoclastic vasculitis, is a term commonly used to denote a small vessel vasculitis. Many possible causes or associations exist for hypersensitivity vasculitis, but a cause or an associated disorder is not found in as many as 50% of patients.
Hypersensitivity vasculitis (a form of small vessel vasculitis) may manifest clinically as cutaneous disease only or it may manifest as skin disease with involvement of other organs. The internal organs most commonly affected in hypersensitivity vasculitis are the joints, gastrointestinal tract, and the kidneys. The prognosis for hypersensitivity vasculitis is good when no internal involvement is clinically present. Hypersensitivity vasculitis may be acute and self-limited, recurrent or chronic. Note the image below.
Circulating immune complexes play a role in the pathogenesis of hypersensitivity vasculitis. Although immune complexes are involved in the pathogenesis of hypersensitivity vasculitis, other autoantibodies, such as antineutrophil cytoplasmic antibody (ANCA), may be associated with disease manifestations, and other inflammatory mediators, adhesion molecules, and local factors may affect the endothelial cells and play a role in the manifestations of this disease. The exact mechanisms causing hypersensitivity vasculitis remain to be elucidated.
The incidence of hypersensitivity vasculitis is unknown, but the condition is presumed to be relatively rare.
Several studies from Spain have been conducted on hypersensitivity vasculitis.[3, 4, 5, 6, 7] Hypersensitivity vasculitis reportedly has an incidence of 10-30 cases per million people per year. Henoch-Schönlein purpura reportedly has an incidence of 14 cases per million people per year.
The prognosis for hypersensitivity vasculitis is generally good, but mortality is possible if the kidneys, the gastrointestinal tract, the lungs, the heart, or the central nervous system is involved. Patients with chronic cutaneous disease may develop ulceration or recurrent painful bouts of purpura. Some hypersensitivity vasculitis patients alter their lives because of recurrent purpuric eruptions or accompanying symptoms.
Hypersensitivity vasculitis is reported most often in the white population, but epidemiologic studies are not available to assess whether hypersensitivity vasculitis is associated with any specific ethnic group or skin type.
Although hypersensitivity vasculitis appears to affect men and women in approximately equal numbers, some of the studies from Spain suggest that hypersensitivity vasculitis is slightly more common in men than in women.
Hypersensitivity vasculitis may occur at any age. In both adults and children, hypersensitivity vasculitis may appear identical to Henoch-Schönlein purpura. A precise differentiation of hypersensitivity vasculitis from Henoch-Schönlein purpura is not possible in this author's view.
Patients with hypersensitivity 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 detectable systemic disease. Vasculitis may occur in conjunction with collagen-vascular disorders, paraproteinemia, ingestants (drugs or foods), infections, or malignancy (rare).[8, 9, 10, 11]
The clinician should elicit information about possible systemic manifestations from patients. Additionally, the clinician should 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 or a 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, as described below and shown in the images that follow :
Urticarial vasculitis. These lesions differ from routine hives by lasting longer (often >24 h), being less pruritic, and often resolving with a bruise....
Erythema elevatum diutinum, a rare cutaneous vasculitis.
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 have been 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 report 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.[14, 15]
Livedo reticularis is a rare manifestation of small-vessel vasculitis. Livedo reticularis 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 medium and large vessels, but it may complicate intense purpura.
Perform a careful physical examination in patients with hypersensitivity vasculitis, including specific observation of cardiopulmonary, musculoskeletal, and gastrointestinal systems.
From one third to one half of cutaneous vasculitis cases are idiopathic; the remainder have a variety of causes, as follows:
Antibiotics are the most common drugs to 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. Hepatitis C is a commonly 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 has been implicated in some cases of vasculitis in the past. HIV infection may also be associated with some cases of cutaneous vasculitis.
Ascertaining whether a drug (eg, antibiotic) or an infection (eg, upper respiratory tract infection) is responsible for the disease is impossible because the occurrence of vasculitis postdates infection and the drug therapy used to treat the infection.
Foods or food additives may cause vasculitis.
Collagen-vascular diseases account for 10-15% of cases of vasculitis. In particular, rheumatoid arthritis, Sjögren syndrome, and lupus erythematosus may have an associated hypersensitivity 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 hypersensitivity 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 hypersensitivity vasculitis.
Small-vessel hypersensitivity vasculitis may be seen uncommonly in patients with a larger-vessel vasculitis, such as Wegener granulomatosis, polyarteritis nodosa, or Churg-Strauss syndrome.
Evaluation of patients with hypersensitivity vasculitis (leukocytoclastic vasculitis) serves 2 purposes: to determine the presence of systemic disease and to identify an associated disorder, which aids in predicting the patient's prognosis. No established routine exists, and testing should be prompted by signs or symptoms.
A urinalysis should be performed in all patients to assess renal disease.
Some authors also include a complete blood cell count, an erythrocyte sedimentation rate, and a blood chemistry panel.
Check the stool for blood in patients with bowel symptoms.
Obtain serologic studies (eg, antinuclear antibody; antineutrophil cytoplasmic antibody [ANCA], ie, circulating ANCA, perinuclear ANCA, atypical ANCA; rheumatoid factor) for patients without an obvious disease cause. In children and perhaps in some adults, serologic testing for a possible streptococcal infection should be considered (Streptozyme or ASO titer).
Complement levels, including total hemolytic complement (CH100 or CH50), C3 levels, and C4 levels, may be obtained for patients suspected of having lupus erythematosus or patients who have urticarial vasculitis.
Include immunofixation electrophoresis (IFE), cryoglobulins, and hepatitis C antibody in tests for paraproteins for patients without otherwise identified disease. Hepatitis B has been associated with vasculitis in the past; however, it appears that the association may have occurred by virtue of co-infection with hepatitis C (previously termed non-A, non-B). The measurement of hepatitis B surface antigen may not be required in all cases. Cryoglobulins are often not obtained properly; a positive rheumatoid factor should suggest the possibility of cryoglobulins.
Perform HIV testing for patients at high risk for infection and possibly for those with otherwise unidentifiable cause of disease.
Consider obtaining direct immunofluorescence microscopy for selected patients. The presence of IgA occurs in Henoch-Schönlein purpura.
Perform a skin biopsy of a relatively fresh (preferably < 24 hours of duration) lesion in most, if not all, adult patients. Biopsies are often not performed in children with suspected vasculitis whose clinical presentation is classic. Consider performing a biopsy of muscle or a biopsy of visceral organs in patients with severe vasculitic syndromes; however, most patients with hypersensitivity vasculitis of the skin do not require such tests.
Obtaining a bone marrow sample may be useful if the peripheral smear is abnormal.
A skin biopsy sample reveals the presence of vascular and perivascular infiltration of polymorphonuclear leukocytes with formation of nuclear dust (leukocytoclasis), extravasation of erythrocytes, and fibrinoid necrosis of the vessel walls. This process is dynamic; a biopsy sample of a lesion too early or too late in its evolution may not reveal these findings.
The picture of hypersensitivity vasculitis is a pattern that can occur in any vasculitic syndrome but may also occur in nonvasculitic diseases (eg, neutrophilic dermatoses), at the base of a biopsy sample of a leg ulceration, or in some insect bite reactions. Careful clinicopathologic correlation is necessary. Note the image below.
Histopathologic features of leukocytoclastic vasculitis.
Once a diagnosis of hypersensitivity vasculitis (leukocytoclastic vasculitis) is established and the patient is fully evaluated, specific or nonspecific management options may be used.
Elevation of the legs or compression stockings may be useful because the disease often affects dependent areas.
Treat the cause in patients with an identifiable cause. Removal of a drug thought to be causing the vasculitis may result in rapid clearing of the process in up to 2 weeks.
Treat chronic disease that primarily involves the skin with nontoxic modalities whenever possible; avoid using systemic corticosteroids and/or immunosuppressive agents. Colchicine[17, 18] or dapsone may be administered for patients with disease of the skin with or without joint manifestations.
Patients with urticarial lesions may be treated with antihistamines (both soporific ones and less sedating agents). Sometimes, a combination of these agents is needed to control disease manifestations. Some patients have responded to nonsteroidal anti-inflammatory agents.
Patients with severe visceral involvement may require high doses of corticosteroids (1-2 mg/kg/d) with or without an immunosuppressive agent (eg, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil).
Rituximab use has been reported in various subsets of vasculitis patients, particularly those with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Several patients with chronic cutaneous small-vessel vasculitis have also been treated effectively with this agent.[19, 20, 21]
Consider a restrictive diet for patients with chronic cutaneous vasculitis without other identifiable causes.
Surgical care is rarely needed for patients with hypersensitivity vasculitis (leukocytoclastic vasculitis). Surgical care may be appropriate if a tumor is identified as a cause of the process. Surgical care also may be appropriate if recalcitrant ulceration occurs after control of active disease.
Has effects against neutrophils, which are probably involved in expression of cutaneous vasculitis; has been demonstrated to be steroid-sparing in open-label studies. The only double-blinded placebo-controlled trial failed to demonstrate its efficacy; however, several methodological errors occurred in this study. Not FDA approved in children.
Small open-label studies or single case reports have suggested that dapsone is effective in some patients with cutaneous vasculitis. Used in hypersensitivity vasculitis not for its antimicrobial activity but for its modulatory effect on neutrophil activity.
Useful in life-threatening cases of vasculitis. Patients with only skin disease generally should not be treated with this agent. Useful in patients with polyarteritis nodosa, Wegener granulomatosis, and Churg-Strauss syndrome. Agent is an alkylating agent that depresses T- and B-cell function.
In hypersensitivity vasculitis (leukocytoclastic vasculitis), inpatient care is needed for patients who have severe vasculitic syndromes with multiple organ dysfunction. Most patients with cutaneous vasculitis are treated in an outpatient setting.
Design of a follow-up program depends on the vasculitic syndrome, its chronicity, and the organ systems affected. Further follow-up care may not be needed once the process is inactive in a patient with hypersensitivity vasculitis.
Patients with Henoch-Schönlein purpura may develop impairment of renal function or hypertension; regular follow-up care, even after complete clearing of disease, is needed.
Management of patients with chronic cutaneous vasculitis is a challenge. Dietary restriction may be tried in absence of an identifiable cause. Colchicine (0.6 mg bid) and/or dapsone (100-200 mg/d) may control disease. Other agents (including immunosuppressive/cytotoxic agents) may be administered in patients with unresponsive or poorly responsive conditions.
The prognosis of patients with cutaneous vasculitis depends on the underlying syndrome or the presence of end-organ dysfunction, as follows:
Patients with disease that primarily affects the skin and/or the joints have a good prognosis.
Patients with Wegener granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, or severe necrotizing vasculitis have a potentially fatal disease. Treatments with corticosteroids and/or immunosuppressive/cytotoxic agents often save the patient's life.
Michelle Pelle, MD, Clinical Assistant Professor, Division of Dermatology, Department of Medicine, University of California, San Diego, School of Medicine
Disclosure: Nothing to disclose.
Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD, Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania