Vasculitis is an inflammatory process affecting the vessel wall and leading to its compromise or destruction and subsequent hemorrhagic and ischemic events. Vasculitis can be classified as a primary phenomenon (e.g. idiopathic cutaneous leukocytoclastic angiitis or Wegener granulomatosis) or as a secondary disorder (connective tissue disease [CTD], infection, or adverse drug eruption-associated vasculitis). Cutaneous vasculitis may present as a significant component of many systemic vasculitic syndromes such as rheumatoid vasculitis or anti-neutrophil cytoplasmic antibody (ANCA)-associated primary vasculitic syndromes (Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis). Cutaneous vasculitis manifests most frequently as palpable purpura or infiltrated erythema indicating dermal superficial, small-vessel vasculitis, and less commonly as nodular erythema, livedo racemosa, deep ulcers, or digital gangrene implicating deep dermal or subcutaneous, muscular-vessel vasculitis. A biopsy extending to the subcutis taken from the most tender, reddish or purpuric lesional skin is the key to obtaining a significant diagnostic result and serial sections are often required for identifying the main vasculitic lesion. Coexistence of pan-dermal small-vessel vasculitis and subcutaneous muscular-vessel vasculitis usually indicates CTD, ANCA-associated vasculitis, Behcet disease, or malignancy-associated vasculitis. A concomitant biopsy for direct immunofluoresence evaluation contributes to accurate diagnosis by distinguishing IgA-associated vasculitis (Henoch-Schonlein purpura) from IgG-/IgM-associated vasculitis, which has prognostic significance. Treatment for cutaneous vasculitis should include avoidance of triggers (excessive standing, infection, drugs) and exclusion of vasculitis-like syndromes (pseudovasculitis) such as thrombotic disorders (e.g. anti-phospholipid antibody syndrome). In most instances, cutaneous vasculitis represents a self-limited condition and will be relieved by leg elevation, avoidance of standing, and therapy with NSAIDs. For mild recurrent or persistent disease, colchicine and dapsone are first-choice agents. Severe cutaneous disease requires treatment with systemic corticosteroids or more potent immunosuppression (azathioprine, methotrexate, cyclophosphamide). A combination of corticosteroids and cyclophosphamide is required therapy for systemic vasculitis, which is associated with a high risk of permanent organ damage or death. In cases of refractory vasculitis, plasmapheresis and intravenous immunoglobulin are viable considerations. The new biologic therapies that act via cytokine blockade or lymphocyte depletion, such as the tumor necrosis factor-α inhibitor infliximab and the anti-B-cell antibody rituximab, respectively, are showing benefit in certain settings such as CTD and ANCA-associated vasculitis.

Clinical approach to cutaneous vasculitis.

OBJECTIVE:To evaluate the literature for published cases of drug-induced vasculitis with cutaneous and/or systemic manifestations.DATA SOURCES:The MEDLINE database was searched from 1965 to December 1999 for articles focusing on drugs and vasculitis, using various search terminologies (e.g., Churg-Strauss syndrome, Goodpasture's syndrome, Henoch-Schonlein purpura, various drugs suspected to induce vasculitis). Cases were included when they met the established criteria as described in the methodology.DATA SYNTHESIS:Drugs found to be most frequently associated with vasculitis were propylthiouracil, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, and methotrexate. The interval between the first exposure and appearance of symptoms was reported to be extremely variable (hours to years). Vasculitis has occurred after drug dosage increases and after rechallenge with the suspected drug. In the majority of cases, vasculitis has resolved after d...

Cutaneous and systemic manifestations of drug-induced vasculitis.

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves' disease. Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves' disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs. These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves' disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves' disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves' disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.

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High Prevalence of Antineutrophil Cytoplasmic Antibody Positivity in Childhood Onset Graves’ Disease Treated with Propylthiouracil

Diffuse alveolar hemorrhage (DAH) in primary and secondary vasculitis occurs when capillaritis is present. The diagnosis of DAH is considered in patients who develop progressive dyspnea with alveolar opacities on chest imaging (with density ranging from ground glass to consolidation) that cannot be explained otherwise. Hemoptysis, a valuable sign, is often absent. A decline of blood hemoglobin level over a few days without hemolysis or any hemorrhage elsewhere should be an alert for DAH. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue. Lung biopsy is not recommended. A search for anti-neutrophil cytoplasmic autoantibodies (ANCAs) is mandatory. Once DAH is diagnosed and hemodynamic as well as infectious causes have been excluded, ANCA-associated vasculitis is taken into account (mainly microscopic polyangiitis or Wegener granulomatosis, and, exceptionally, Churg-Strauss syndrome). Drug-induced DAH, especially antithyroid drugs such as propylthiouracil may be coupled with ANCA. Isolated DAH with capillaritis with or without ANCA is rare. DAH in systemic lupus erythematosus is either associated or not with capillaritis. Treatment of DAH should target the underlying disorder. In the primary vasculitides, corticosteroids and immunosuppressants, especially cyclophosphamide, are the mainstay of therapy, but plasma exchange, particularly in severe DAH, is the rule, although evidence of its effectiveness is awaited.

Alveolar Hemorrhage in Vasculitis (Primary and Secondary)

Objective Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with propylthiouracil (PTU). The appearance of MPO-ANCA in these cases was suspected of being related to PTU because the titres of MPO-ANCA decreased when PTU was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during PTU therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. Patients We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting PTU therapy. Twenty-nine of them were later excluded because of adverse effects of PTU or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). Measurements MPO-ANCA was measured at intervals of 2-6 months. Results Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of PTU therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued PTU therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher fever, oral ulcers and polyarthralgia, but the symptoms resolved 2 weeks after stopping PTU therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing PTU. Conclusions PTU therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis.

Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with propylthiouracil and the relationship between MPO-ANCA and clinical manifestations

We present a case study of a 52-year-old female patient with hyperthyroidism which had been diagnosed at the age of 35. However, the malfunction of thyroid had been poorly controlled. Thyroid function was returning to normal after the administration of propylthiouracil (PTU) 300 mg/day, however purpura appeared in both lower extremities. Renal function deteriorated rapidly, and the patient was admitted to our hospital. According to the biopsies, leukocytoclastic vasculitis in the skin was apparent, and crescent formation was observed in the glomerulus. Serological examination revealed positive antineutrophil cytoplasmic autoantibodies (ANCA) against proteinase 3 (Pr3) and myeloperoxidase (MPO). Antinuclear autoantibody was positive. After cessation of PTU and administration of prednisolone, the purpura disappeared and ANCA were becoming negative. Renal function recovered gradually. Thyroid function was kept within normal range using iodine solution. Thus, it is strongly suggested that PTU-induced rapidly progressive glomerulonephritis associated with ANCA.

Kudoh Y

Papers

Propylthiouracil-induced rapidly progressive glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies.