Leukocytoclastic Vasculitis (Hypersensitivity Vasculitis)

Article Author:
Dana Baigrie
Article Editor:
Jonathan Crane
Updated:
2/17/2018 8:13:32 PM
PubMed Link:
Leukocytoclastic Vasculitis (Hypersensitivity Vasculitis)

Introduction

Leukocytoclastic vasculitis, also known as “hypersensitivity vasculitis” is a histopathologic diagnosis given to cutaneous, small vessel vasculitis, specifically a vasculitis of the dermal post-capillary venules. The vasculitis is most often idiopathic. However, there are many other triggers including, but not limited to, infections, neoplasms, inflammatory disorders, and drug-induced vasculitis. Key clinical features of leukocytoclastic vasculitis include palpable purpura, lower extremity location, small vessel involvement, and extracutaneous involvement in approximately 30% of patients.

If leukocytoclastic vasculitis is suspected, a punch biopsy should be performed with direct immunofluorescence studies. If no systemic symptoms are present, laboratory testing including ESR, complete blood count (CBC), basic metabolic panel, liver function tests, and urinalysis should be done as well. If there is a concern for systemic involvement, a more extensive workup can be performed.

Most cases of cutaneous, small vessel vasculitis are self-limited with 90% resolving in weeks to months of onset. Otherwise, treatment depends on the severity of disease and can range from an oral corticosteroid taper to various steroid-sparing agents.

Etiology

Leukocytoclastic vasculitis may be triggered by a variety of different factors, though approximately half of cases are idiopathic. The triggering factors include infections, certain drugs or chemicals, systemic disease, or neoplastic disease. Aside from idiopathic etiology, infections and drugs are the most common triggers. 

Of the infectious triggers, streptococcal upper respiratory tract infection is the most common. Other infectious triggers include, but are not limited to, Mycobacterium, hepatitis B and C, Staphylococcus aureus, Chlamydia, Neisseria, and HIV. 

There are many drug etiologies of cutaneous small vessel vasculitis. The onset is typically 1 to 3 weeks after drug initiation. These include, but are not limited to, beta-lactams, erythromycin, clindamycin, vancomycin, sulfonamides, furosemide, allopurinol, NSAIDs, amiodarone, gold, thiazides, phenytoin, beta-blockers, TNF-alpha inhibitors, selective serotonin reuptake inhibitors, metformin, warfarin, valproic acid, among many others.

Neoplastic or hematologic triggers of leukocytoclastic vasculitis include, but are not limited to, lymphomas, leukemias, visceral tumors such as intestinal adenocarcinoma and lung cancer. 

Systemic diseases including connective tissue diseases (lupus, dermatomyositis, and Sjogren), inflammatory bowel disease, Behcet disease, and rheumatoid arthritis have been implicated in leukocytoclastic vasculitis.

Thrombotic, embolic, and cryoglobulinemia are also documented triggers of cutaneous small vessel vasculitis.

Epidemiology

Leukocytoclastic vasculitis occurs in all ages and both genders; however, it typically presents in adults. The annual incidence of biopsy-proven leukocytoclastic vasculitis is approximately 45 per million individuals. Henoch-Schonlein purpura (HSP) is the most common form of vasculitis in children, with an incidence of up to 270 cases per million children per year. Children affected by HSP average 6 years of age and have a slight male predominance.

Pathophysiology

The pathogenesis of leukocytoclastic vasculitis involves immune complex deposition in small vessel walls in addition to activation of the complement system. Neutrophils are recruited, and injury to vessel walls ensues with secondary exudation of erythrocytes, fibrin, and serum. Fibrinoid necrosis of small vessel walls will be noted secondary to lysosomal enzymes such as collagenases and elastases as well as reactive oxygen species. Lymphokines aid in the evolution of the clinical findings as well. IL-1, IL-6, IL-8, and tumor necrosis factor are increased in circulation. Turbulence and increased venous pressure present in the lower extremities can elucidate why leukocytoclastic vasculitis commonly tends to occur on the legs.

Histopathology

The histopathologic features of leukocytoclastic vasculitis will vary based on the time frame of the vasculitis. To observe the most diagnostic findings is best to biopsy a lesion in the first 18 to 24 hours of onset. In this stage, classically leukocytoclastic vasculitis demonstrates neutrophil infiltration into small venule vessel walls. The neutrophils will undergo degeneration, known as leukocytoclasis with nuclear dust (karyorrhexis). Fibrinoid necrosis of the vessel walls will be apparent around the vasculature. Extravasation of red blood cells will be present in the dermis as well. In drug-related cases, eosinophils are often noted in the dermis.

While some studies suggest that direct immunofluorescence is not useful in diagnosis unless performed on fresh lesions less than 6 hours old, more recent studies indicate that C3, fibrinogen, and IgM may be noted in a granular pattern within vessel walls. If IgA is noted on direct immunofluorescence, this strongly predicts renal disease.

History and Physical

The cutaneous manifestations of leukocytoclastic vasculitis usually appear about a week after the triggering event. Leukocytoclastic vasculitis presents as erythematous macules with palpable purpura bilaterally on dependent areas of the body like the lower extremities. Unilateral presentations and localized lesions are rare. Hemorrhagic vesicles and bulla, pustules, nodules, crusted ulcers, or livedo reticularis may also be present on physical exam. The lesions range in size from 1 mm to 1 cm in diameter. The lesions can appear at once in crops, or various crops may cycle and produce lesions with different stages of evolution. Koebnerization, the appearance of lesions at areas of trauma, is uncommon with this vasculitis. In fact, reverse koebnerization has been described with the disappearance of the lesions with pressure bandage application after the biopsy. The lesions are asymptomatic but may itch, burn, or sting.

Extracutaneous manifestations with leukocytoclastic vasculitis are not uncommon. Systemic symptoms noted with leukocytoclastic vasculitis may include low-grade fevers, malaise, weight loss, myalgias, and arthralgias. These findings have been noted in approximately 30% of affected patients, with arthralgias compromising the most common manifestation. Other less common manifestations include renal, gastrointestinal, pulmonary, or neurological symptoms, and these entities may be better classified as microscopic polyangiitis/polyarteritis.

Henoch-Schonlein purpura is a specific form of cutaneous small vessel vasculitis that typically affects children and proceeds an upper respiratory tract infection. This disease involves vascular IgA deposition. The clinical features include palpable purpura, abdominal pain, hematuria/renal disease, and arthritis.

Evaluation

If leukocytoclastic vasculitis is suspected, a punch biopsy should be performed preferably in the first 24 to 48 hours of lesion onset when the diagnostic yield of the biopsy is greatest. Also, direct immunofluorescence should be performed to evaluate for the presence of immunoglobulins, as this may have an impact on disease course.

A general workup, if there is no concern systemic involvement, should include ESR, CBC, and basic metabolic panel to rule out renal disease, liver function tests, and urinalysis to check for hematuria and proteinuria. A more extensive workup can be completed if systemic involvement is a concern including a hepatitis panel, HIV testing, ASO titer (if a streptococcal infection is the suspected trigger, chest x-ray, ANA, rheumatoid factor, serum complement, SPEP/UPEP, and cryoglobulins.

Treatment / Management

The mortality rate of leukocytoclastic vasculitis is low (about 2%), and related to systemic involvement versus strictly cutaneous involvement. Approximately 90% of patients experience spontaneous resolution of their skin lesions within weeks to months, with the remaining 10% continuing to chronic disease averaging 2 to 4 years. Arthralgias without fever may portend chronicity. 

Mild cases can be treated with supportive measures such as leg elevation, rest, compression stockings, and antihistamines. Systemic corticosteroids may be used in chronic or more severe cases related to medications to ameliorate the disease progression and help improve the vasculitis. A tapering high-dose of 1 mg/kg per day is recommended over 4 to 6 weeks.

In idiopathic or chronic cases, certain steroid-sparing medications such as dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, and intravenous immunoglobulin (IVIG) may be indicated. 

Drug and infection-induced vasculitis respond to discontinuation of the offending medication and treatment of the infection.