The treatment of choice of LV associated with HCV is interferon alfa, which has been shown in randomized trials to improve dermatologic, renal, and joint manifestations, as well as to reduce cryoglobulin levels.25-27 For cryoglobulinemic vasculitis not associated with HCV, other agents such as colchicine, cyclosporine, melphalan, and intravenous immunoglobulin have been tried.25,28-30 For hepatitis B vasculitis associated with polyarteritis nodosa, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and high-dose corticosteroids have been used.31-32
Drug-induced LV is the final major etiology; in fact, LV also is known as hypersensitivity vasculitis, allergic vasculitis, or allergic angiitis resulting from various endogenous antigens and exogenous factors associated with connective tissue diseases, malignancies, infections, and chemicals or drugs.17 LV also has been reported to be associated with prolonged exercise,33 radio contrast media,34 dyes,35 food additives,36,37 and various medications (eg, sulfonamides components, antibiotics, nonsteroidal anti-inflammatory drugs.).17 Drug-induced LV presents as palpable purpura confined to the lower extremities. The mechanism for the development of drug-induced LV is postulated to involve a cascade of immune complex formation and complement activation. The onset of LV typically occurs 7 to 10 days after contact with the antigen responsible for the reaction but may occur as early as several hours and as late as several months after exposure.11,17 The histopathology of drug-induced LV shows confinement to superficial vascular plexus, infiltration of vessel walls with neutrophilic leukocytes and nuclear dusts, lymphocytes, erythrocyte extravasation, and fibrinoid necrosis.
At the onset of the reaction, in patients with a history of taking medications, one study reported the presence of extravenular eosinophils in 33% of patients diagnosed with a hypersensitivity vasculitis compared with none in patients with Henoch-Schönlein purpura.38 The timing of the biopsy also is significant because early lesions are more likely to demonstrate positive immunofluorescence for IgM, IgG, and C3 near the vessel wall. IgA and fibrinogen are reported to be less commonly found. The optimal lesions on which to perform a biopsy are those that are 18- to 24-hours old.17
After the diagnosis of LV is confirmed with clinical presentation and a biopsy result of an involved lesion, the cause is determined by the patient's history and various laboratory testing. An effort is made to remove or treat the underlying infectious, inflammatory, or neoplastic etiology. Medications have been reported to cause about 10% to 24% of the cutaneous manifestations of LV.1,17 Mild forms of LV may not require further treatment other than removal of the causative agent. Pharmacologic treatments include topical and systemic corticosteroids, immunosuppressants,17 antihistamines,12,17 and nonsteroidal anti-inflammatory drugs,17 all of which have been used with varying degrees of efficacy. Systemic corticosteroid therapy and immunosuppressants are indicated in patients with rapidly progressing vasculitis or in severely ill patients with renal disease.17
Retrospective evaluation and comparison of case reports of LV and cutaneous eruptions associated with coumarin derivatives (Table 1) are difficult because some reports are purely descriptive and lack laboratory and biopsy data. The morphology and distribution of skin lesions in our patients were similar to previously reported LV cases. Timing of the drug reaction is an important issue in our 4 patients considering that 2 to 10 years elapsed between initiation of warfarin and the onset of the cutaneous manifestations. To our knowledge, there have been no other reports of LV occurring years after initiating warfarin therapy. Another notable difference in our patients was the long period between initiation of warfarin and the onset of the lesions during rechallenge (Table 2). Recurrence of lesions has been reported from 6 hours to 6 days after rechallenge (Table 1). In our patients, recurrence of the lesions occurred 5, 11, and 23 days after rechallenge.
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It also may be possible that other events or factors may have contributed to LV reactions in our patients, as it can be argued that elevated cryoglobulins (patients 2 and 4) may have had an association. Although the possibility exists, it seems unlikely to have been the primary cause because LV associated with cryoglobulins is more likely a long-term and persistent reaction rather than a reaction that resolves with cessation of a drug.39 Additionally, cryoglobulins involved in immune complex reactions have frequently been found in patients with hypersensitivity vasculitis.39
Infection did not seem to be a likely culprit in at least 3 of our patients. In patient 1, who had a history of recurrent urinary tract infections, the reaction resolved with the withdrawal of warfarin therapy. There was no evidence of an infection around the time of the reaction. In patient 4, an increased neutrophil count was noted, and a case could be made for the possibility of an underlying infection as a contributing factor. However, the patient was found to have a urinary tract infection after the warfarin was discontinued while skin lesions were improving.