Hypersensitivity Vasculitis

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Background

Hypersensitivity vasculitis, which is usually represented histopathologically as leukocytoclastic vasculitis (LCV), is a term commonly used to denote a small-vessel vasculitis. There are many potential causes of hypersensitivity vasculitis; however, up to 50% of cases are idiopathic.

Hypersensitivity vasculitis may present clinically as cutaneous disease only or it may manifest as skin disease with systemic involvement. The internal organs most commonly affected in hypersensitivity vasculitis are the joints, gastrointestinal tract, and kidneys. Hypersensitivity vasculitis may be acute and self-limited, recurrent, or chronic. Overall, hypersensitivity vasculitis has a favorable prognosis, particularly when no internal involvement is present. Note the image below.


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Hypersensitivity vasculitis.

Pathophysiology

Hypersensitivity vasculitis is thought to be mediated by immune complex deposition.[1] In this form of vasculitis, circulating antigens in the body (produced by factors such as medications, infections, and neoplasms) induce antibody formation. These antibodies bind to the circulating antigen and create immune complexes, which then deposit within vessels, activating complement and inducing inflammatory mediators. Inflammatory mediators, adhesion molecules, and local factors may affect the endothelial cells and may play a role in the manifestations of this disease.[2]

Additionally, autoantibodies, such as antineutrophil cytoplasmic antibody (ANCA), may be associated with disease manifestations. In ANCA-mediated vasculitis, intracellular proteins from neutrophils become expressed on the cell surface, leading to formation of antibodies (ANCA). These autoantibodies then bind neutrophils, subsequently leading to neutrophil adhesion to vessel walls and cellular activation. Overall, however, the exact mechanisms causing hypersensitivity vasculitis remain to be elucidated.

Epidemiology

Frequency

United States

The incidence of hypersensitivity vasculitis is unknown, but the condition is presumed to be relatively rare.

International

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 (HSP), a small-vessel vasculitis characterized by deposition of immunoglobulin A (IgA) immune complexes, reportedly has an incidence of 14 cases per million people per year.

Mortality/Morbidity

The prognosis for hypersensitivity vasculitis is generally good, with most patients experiencing spontaneous resolution within weeks to months. Some patients develop a relapsing disease course, admixed with symptom-free periods. A subset of patients (< 10%) can develop chronic, unremitting disease with recurrent episodes of painful purpura and even ulceration, which can have a considerable impact on quality of life.[8, 9] There is increased morbidity and the potential for mortality if the kidneys, gastrointestinal tract, lungs, heart, or central nervous system are involved.

Race

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.

Sex

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.[7]

Age

Hypersensitivity vasculitis may occur at any age. In both adults and children, Henoch-Schönlein purpura (HSP) may present in a clinically identical fashion to hypersensitivity vasculitis, and biopsy with direct immunofluorescence is typically needed to distinguish the two. HSP is a specific small-vessel vasculitis associated with the presence of vascular IgA deposition. However, by definition, HSP is a clinically defined entity and some authorities may make this diagnosis even if IgA deposition is absent. The classic tetrad of HSP consists of palpable purpura, arthritis, abdominal pain, and hematuria. HSP typically follows a respiratory infection and is more common in the pediatric population.

History

Cutaneous lesions of hypersensitivity vasculitis are often asymptomatic, although patients may report itching, burning, or pain. Vasculitis may occur as a cutaneous eruption only or in conjunction with collagen-vascular disorders, paraproteinemia, ingestants (drugs or foods), infections, or malignancy.[10, 11, 12, 13]

The clinician should perform a complete review of systems to elicit possible systemic manifestations, inquiring about symptoms such as fever, arthralgia, arthritis, myalgia, abdominal pain, diarrhea, hematochezia, cough, hemoptysis, sinusitis, paresthesia, weakness, and hematuria. In addition, the clinician should determine whether the patient has started any new medications or has changed the dosage of any existing medications. The clinician should also inquire about intravenous drug use, hepatitis, transfusion, and travel history. An underlying diagnosis such as inflammatory bowel disease or collagen-vascular disease, particularly rheumatoid arthritis, lupus erythematosus, or Sjögren syndrome ,should also be considered.

Physical

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.[14]


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Henoch-Schönlein purpura.


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Urticarial vasculitis. These lesions differ from routine hives by lasting longer (often >24 h), being less pruritic, and often resolving with a bruise....


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Erythema elevatum diutinum, a rare cutaneous vasculitis.

Palpable purpura is the most frequent presentation of small-vessel vasculitis. Lesions are usually round, 1-3 mm in diameter, and may coalesce to form plaques. Purpuric lesions are sometimes barely palpable. Palpable purpura favor dependent areas and therefore are most frequently observed on the legs. However, any surface can be involved, particularly areas affected by trauma (Koebner phenomenon) or areas under tight-fitted clothing.

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.[15]

Urticarial lesions may occur in some patients, which can occasionally predate purpuric lesions. Urticarial lesions in hypersensitivity vasculitis are of a different character than routine urticaria. They tend to be of longer duration (often >24 h) and are more likely to resolve with residual pigmentation or ecchymosis. Patients often report a burning sensation rather than pruritus. To determine the duration of individual lesions, the clinician can encircle several individual lesions and ask the patient to observe them periodically and note when the lesions resolve or change shape and when a new lesion forms outside the encircled area.

A recent retrospective study of 766 patients with cutaneous vasculitis found that 21 patients had urticarial vasculitis (2.7%). Among the cases of urticarial vasculitis, potential precipitating factors included upper respiratory tract infections and penicillin in 4 patients (all younger than 20 y), HIV in 1 patient, and malignancy in 1 patient. Two patients demonstrated hypocomplementemia.[16]

Patients with hypocomplementemic urticarial vasculitis syndrome may develop chronic obstructive pulmonary disease, uveitis or episcleritis, glomerulonephritis, recurrent abdominal pain, and, rarely, cardiac and central nervous involvement, requiring a thorough physical examination.[17, 18]

Livedo reticularis or racemosa are rare manifestations of small-vessel vasculitis. These clinical findings are more frequent in patients with occlusive or inflammatory disease of medium-sized vessels.

Nodular lesions are more common in medium-vessel vasculitis, but may also occur in patients with small-vessel vasculitis.

Ulceration is also more common in medium- and large-vessel vasculitis, but it may complicate intense purpura or bullous lesions associated with small vessel vasculitis.

Perform a careful physical examination in patients with hypersensitivity vasculitis, including specific observation of cardiopulmonary, musculoskeletal, and gastrointestinal systems.

Causes

One third to one half of cutaneous vasculitis cases are idiopathic; the remainder have a variety of causes

Antibiotics are the most common drugs to cause hypersensitivity vasculitis, particularly beta-lactams. Nonsteroidal anti-inflammatory drugs and diuretics also frequently cause vasculitis. However, almost all drugs and drug additives are potential causes.[19, 20] Hydralazine, minocycline, propylthiouracil, and levamisole-adulterated cocaine use should be considered in patients with ANCA-associated vasculitis.[21]

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, likely secondary to the presence of cryoglobulins. However, when 1614 patients with hepatitis C were studied, 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.

Occasionally, 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 both the infection and the drug therapy used to treat the infection.

Foods or food additives may also cause vasculitis.

Collagen-vascular diseases account for 10-15% of cases of cutaneous 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 1-5% of cases of cutaneous hypersensitivity vasculitis. Lymphoproliferative diseases are more common (particularly hairy cell leukemia); however, any type of tumor at any site may be related to cutaneous vasculitis. Effective management of malignancy can lead to resolution of the hypersensitivity vasculitis.[22]

Small-vessel hypersensitivity vasculitis may be seen uncommonly in patients with a larger-vessel vasculitis, such as granulomatosis with polyangiitis (formerly Wegener granulomatosis ), polyarteritis nodosa, or eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome ).[23]

Laboratory Studies

Evaluation of patients with hypersensitivity vasculitis (leukocytoclastic vasculitis) serves 2 purposes: (1) to determine the presence of systemic disease and (2) to identify a potential associated disorder, which can provide prognostic information. Currently, no established routine exists for the workup of hypersensitivity vasculitis; therefore, testing should be prompted by clinical signs and symptoms.

A urinalysis should be performed in all patients to assess for renal disease.

Some authors also include a complete blood cell count, an erythrocyte sedimentation rate or C-reactive protein, and a blood chemistry panel.

Fecal occult blood testing should be considered in all patients with hypersensitivity vasculitis and should be performed in at least those with bowel symptoms.

Serologic studies (eg, antinuclear antibody; antineutrophil cytoplasmic antibody [ANCA], ie, circulating ANCA, perinuclear ANCA, atypical ANCA; rheumatoid factor) should be obtained in 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 in patients suspected of having lupus erythematosus or urticarial vasculitis.

Serum protein electrophoresis and immunofixation electrophoresis (IFE) to assess for paraproteinemia, cryoglobulins, and hepatitis C antibody should be included for patients without an otherwise-identified cause of hypersensitivity vasculitis. 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.

HIV testing for patients at high risk for infection and possibly for those with otherwise unidentifiable cause of disease should be considered.

Consider obtaining a skin biopsy for direct immunofluorescence microscopy, which can aid in distinguishing Henoch-Schönlein purpura (HSP) (IgA-associated vasculitis) from other small-vessel vasculitis, which has prognostic significance.

Imaging Studies

Consider the following imaging studies:

Other Tests

Obtain pulmonary function tests for patients with hypocomplementemic urticarial vasculitis syndrome. Also refer these patients to an ophthalmologist to evaluate for uveitis and episcleritis.

Procedures

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 in whom the clinical presentation is classic. If Henoch-Schönlein purpura (HSP) is suspected, early biopsy with direct immunofluorescence (DIF) is warranted to assess for perivascular deposition of IgA. 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.

Histologic Findings

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.


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Histopathologic features of leukocytoclastic vasculitis.

Medical Care

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 causative drug may result in rapid clearing of the process in as little as 2 weeks.

Treat chronic disease that primarily involves the skin with nontoxic modalities whenever possible; avoid using systemic corticosteroids and/or immunosuppressive agents. Colchicine[24, 25] 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 sedating and less sedating agents). Sometimes, a combination of these agents is needed to control disease manifestations. Some patients have also responded to nonsteroidal anti-inflammatory agents. However, a trial of colchicine or dapsone may be required for disease control.

Patients with bullous or ulcerating disease often require a short course of systemic corticosteroids to more rapidly achieve disease control

Patients with progressive or chronic cutaneous disease may require systemic corticosteroids and/or steroid-sparing agents such as azathioprine, methotrexate, or mycophenolate mofetil.

Patients with severe visceral involvement may require high doses of systemic corticosteroids (1-2 mg/kg/day) with or without a steroid-sparing 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.[26, 27, 28]

Patients without other identifiable causes for hypersensitivity vasculitis can consider a restrictive/elimination diet, which can rarely identify a causative agent.[29]

Surgical Care

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.

Consultations

Diet

No specific diet is required. A restrictive/elimination diet may be used for up to 2 weeks for diagnostic and therapeutic purposes.[29]

Activity

No specific restrictions on activity are recommended. Leg elevation, however, may be helpful in patients with hypersensitivity vasculitis.

Medication Summary

No standard therapeutic protocol exists for hypersensitivity vasculitis. In addition, few of the therapies currently used for this entity have been tested in controlled trials.

Colchicine

Clinical Context:  Has effects against neutrophils, which are involved in the pathogenesis of hypersensitivity 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.

Dapsone (Avlosulfon)

Clinical Context:  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.

Class Summary

These agents decrease inflammatory responses and systemically interfere with events leading to inflammation.

Prednisone (Deltasone)

Clinical Context:  Indicated for vasculitis affecting internal organs (eg, kidneys, lungs, CNS). Patients with bullous skin lesions require corticosteroid therapy in order to prevent cutaneous ulceration.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Useful in life-threatening cases of vasculitis. Patients with skin-limited disease generally should not be treated with this agent. Useful in patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis), polyarteritis nodosa, or eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). Agent is an alkylating agent that depresses T- and B-cell function.

Azathioprine (Imuran)

Clinical Context:  Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Methotrexate (Folex, Rheumatrex)

Clinical Context:  Methotrexate inhibits 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) tranformylase, which leads to increased levels of adenosine. This increase in adenosine inhibits leukocyte accumulation, thereby decreasing inflammation.[30, 31] Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).

Adjust dose gradually to attain satisfactory response.

Rituximab (Rituxan)

Clinical Context:  Genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

Immunomodulates response against malignant cells.

Mycophenolate (CellCept)

Clinical Context:  Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Class Summary

These agents inhibit cell growth and proliferation. Note the clinical guideline summary, Guidelines for prescribing azathioprine in dermatology.

Further Inpatient Care

In hypersensitivity vasculitis (leukocytoclastic vasculitis), inpatient care is needed for patients who have severe vasculitic syndromes with organ dysfunction. Most patients with cutaneous vasculitis are treated in an outpatient setting.

Further Outpatient Care

Design of a follow-up program depends on the vasculitic syndrome, its chronicity, and the organ systems affected. For some patients with hypersensitivity vasculitis, further follow-up care may not be needed once the process is inactive.

Patients with Henoch-Schönlein purpura may develop impairment of renal function or hypertension even after complete clearance of their skin disease; therefore, regular follow-up care is needed.[32]

Inpatient & Outpatient Medications

Management of patients with chronic cutaneous vasculitis is a challenge. Colchicine (0.6 mg bid) and/or dapsone (100-200 mg/d) may be effective and are often considered first-line systemic therapies for chronic skin-predominant vasculitis. Other agents (including immunosuppressive/cytotoxic agents) may be administered in patients with unresponsive or poorly responsive conditions. Dietary restriction may be attempted in absence of an identifiable cause.

Transfer

Consider transfer to a tertiary care facility for specialty care in patients with severe visceral disease or chronic unremitting cutaneous disease.

Complications

Vasculitis may be complicated by ulceration of skin or by end-organ dysfunction.

Prognosis

The prognosis of patients with cutaneous vasculitis depends on the underlying syndrome and the presence of end-organ dysfunction, as follows:

Author

Mital Patel, MD, Clinical Fellow in Dermatology/Rheumatology, Brigham and Women's Hospital, Harvard Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Auxillium Honoraria Consulting; Stiefel, a GSK company Honoraria Consulting; UpToDate Honoraria author/editor; JAMA Dermatology Honoraria Associate editor and intermittent author; Elsevier Royalty Book author/editor; Stock holdings in various trust accounts include some pharmaceutical companies and device makers I do not control these accounts, but have directed our managers to divest pharmaceutical stocks as is fiscally prudent I inherited these trust accounts

Ruth Ann Vleugels, MD, MPH, Assistant Professor of Dermatology, Harvard Medical School; Associate Physician, Department of Dermatology, Brigham and Women's Hospital; Associate Physician, Department of Immunology and Allergy, Children's Hospital Boston

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

References

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Hypersensitivity vasculitis.

Henoch-Schönlein purpura.

Urticarial vasculitis. These lesions differ from routine hives by lasting longer (often >24 h), being less pruritic, and often resolving with a bruise or residual pigmentation.

Erythema elevatum diutinum, a rare cutaneous vasculitis.

Histopathologic features of leukocytoclastic vasculitis.

Hypersensitivity vasculitis.

Henoch-Schönlein purpura.

Histopathologic features of leukocytoclastic vasculitis.

Urticarial vasculitis. These lesions differ from routine hives by lasting longer (often >24 h), being less pruritic, and often resolving with a bruise or residual pigmentation.

Erythema elevatum diutinum, a rare cutaneous vasculitis.