Hydralazine was immediately discontinued, and the patient was started on 65 mg daily of intravenous methylprednisolone; methylprednisolone was later changed to oral prednisone 30 mg daily. Due to multiple organ involvement—lung and kidney—intravenous rituximab 375 mg/m2 every week for 4 weeks, per lymphoma protocol, was started. Within 2 weeks of beginning therapy, her renal function and respiratory status improved, and by week 4, the skin lesions had completely resolved. Although initially she did well on immunosuppressive therapy with resolution of all symptoms, the patient contracted Clostridium difficile–induced systemic inflammatory response syndrome after 5 weeks of therapy and died.
Hydralazine was first introduced in 1951 for adjunctive hypertension therapy due to its vasodilation effects.1-3 Since its introduction, it has been implicated in 2 important disease processes: HIAV and hydralazine-induced lupus.
Hydralazine-induced ANCA vasculitis was first documented in 1980; by 2011, multiple cases had been reported.1-7 Hydralazine-induced ANCA vasculitis has occurred in patients aged 11 to 79 years taking 50 to 300 mg daily. Symptom onset varies from 6 months to 14 years, with a mean exposure duration of 4.7 years and mean daily dose of 142 mg.1-7
Clinical manifestations range from less specific, such as fever, malaise, arthralgia, myalgia, and weight loss, to single tissue or organ involvement that may be fatal. The most frequent clinical features include kidney involvement (81%), cutaneous vasculitis (25%), arthralgia (24%), and pleuropulmonary involvement (19%). Cutaneous manifestations include but are not limited to palpable lower extremity purpura; morbilliform eruptions; and hemorrhagic blisters on the lower legs, arms, trunk, nasal septum, and uvula.1-4,8
The most commonly affected organ is the kidney, which commonly presents as hematuria, proteinuria, and elevated serum creatinine level. Histopathologically, patients most likely will have necrotizing and crescentic glomerulonephritis that is pauci-immune by immunofluorescence.7,9 The lungs are the next most commonly affected organ, with a classic presentation of cough, dyspnea, and hemoptysis in the setting of intra-alveolar hemorrhage.6,8 When both the kidneys and lungs are involved, the patient is said to have pulmonary-renal syndrome that is characterized by lung infiltrates or nodules with or without hemorrhage, hemoptysis, and pleuritis in the setting of glomerulonephritis.1,6
Clear data on incidence and prevalence of HIAV does not exist due to the rarity of the disease and the lack of prospective studies. To identify a clear incidence and prevalence, prospective longitudinal studies with larger cohorts along with better recognition and diagnosis are needed.2,8,10 A few predisposing risk factors have been identified, including older age, a cumulative dose of 100 g at the time of presentation, female sex, a history of thyroid disease, HLA-DR4 genotypes, slow hepatic acetylation, and the null gene for C4.1,3,5,9-11 Our patient was an older woman with a history of thyroid disease who had been taking oral hydralazine 75 mg 3 times daily for 13 months. During this 13-month duration, she had no dose adjustments.
Currently, the pathomechanism for HIAV is unclear and may be multifactorial. There are 4 main theories2,8-10,12,13:
1. Hydralazine and its metabolites accumulate inside neutrophils, then subsequently bind and alter the configuration of myeloperoxidase (MPO). This alteration leads to spreading of the autoimmune response to other autoantigens, making neutrophil proteins (eg, elastase, lactoferrin, nuclear antigens) immunogenic.
2. Hydralazine binds MPO in neutrophils, creating cytotoxic products that induce neutrophil apoptosis. Neutrophil apoptosis without priming then results in ANCA antigen presence on the neutrophil cell membrane and the formation of MPO-ANCA. Myeloperoxidase-ANCA then binds to these membrane-bound antigens that cause self-perpetuating, constitutive activation through cross-linking with proteinase 3 or MPO and Fcγ receptors.
3. Activated neutrophils in the presence of hydrogen peroxidase release MPO that converts hydralazine into a cytotoxic product that is immunogenic for T cells that activate ANCA-producing B cells.
4. Histone H3 trimethyl Lys27 (H3K27me3) levels are perturbed in HIAV, which leads to aberrant gene silencing of proteinase 3 and MPO.In contrast, the demethylase Jumonji domain-containing protein 3 for the H3K27me3 histone is increased in patients without HIAV. Based on this data and the data showing a role for hydralazine in reversing epigenetic silencing of tumor suppressor genes in cancer cells,13 it has been proposed that hydralazine may reverse epigenetic silencing of proteinase 3 and MPO.
Diagnosing HIAV is still difficult because physicians do not recognize the drug as the etiologic agent, there is extensive variability in duration between starting the drug and onset of symptoms, and there often is a failure to order the appropriate laboratory and invasive tests needed for evaluation and diagnosis.3,5,8,10,12 Despite these difficulties, a set of criteria and practices for diagnosis are delineated in Table 1, with the key diagnostic feature being resolution with hydralazine cessation.1,5,7,8,12
