had a substantial increase in hydralazine prescriptions with the yearly number increasing by over 40,000 from 2013-2020 , representing more than a 210 % increase for Medicare part D patients . 9
Hydralazine-induced lupus was first reported in 1953 , and subsequent studies have documented this complication in 5-20 % of patients , depending on the dose and duration of use . 10-13 By contrast , hydralazine-induced vasculitis was not reported until 1980 . The initial report described two patients with cutaneous vasculitis , and the following year two cases of hydralazine-induced renal vasculitis were reported . 14-16 Ten years later hydralazine was linked to ANCA-associated vasculitis , but hydralazine-induced pulmonary-renal syndrome was not reported until 2009 . 13
Drug-induced autoimmunity depends on the inciting agent and host genetics . Autoantibody production may occur from direct immunogenicity to the drug or its metabolite alone or after it binds to host proteins . Drug-induced lupus is the most common manifestation of this process and accounts for 10 % of systemic lupus cases . 17 Hydralazine-induced autoimmune disease is thought to involve direct inhibition of protein kinase pathways resulting in decreased DNA methylation of T-lymphocytes . This may lead to overexpression of lymphocyte function-associated antigen 1 , CD70 , and perforin , which disrupts peripheral immune tolerance and causes T-lymphocyte autoreactivity and cytotoxicity . Hydralazine may also interact with aldehyde groups on macrophages leading to activation and cytokine production , stimulating natural killer cell proliferation and the release of cytokines that lead to auto-immunogenicity . 17
Risk factors for hydralazine-induced lupus include higher dose and longer duration of use , female sex , slow acetylation of hydralazine , human leukocyte antigen ( HLA ) DR4 serotype , null allele for C4 complement factor , and family history of autoimmune disorders . 11 , 13 A case-control study underscored the importance of slow acetylation and the DR4 serotype , with 96 % and 73 % of hydralazine-induced lupus patients having these features , respectively . 18 Arthralgia and myalgia are the most common manifestations reported by these patients , with fever , malaise , and weight loss being less common . More severe cases may have glomerulonephritis , but this is only seen in 5-10 % of patients . 12 ANA positivity varies between 50-90 %, with anti-histone antibody positivity in up to 95 % cases . Anti-double stranded DNA antibody is rare (< 5 % of cases ). Hydralazine-induced lupus has a generally favorable prognosis , often reversing with discontinuation of hydralazine . 11 Less is known about the pathogenesis of hydralazine-induced vasculitis , but hydralazine appears to accumulate in neutrophils , bind to myeloperoxidase ( MPO ), and produce cytotoxic molecules that lead to apoptosis and the resultant necrotizing vasculitis of small vessels . 17 However , ANCA positivity without vasculitis has also been associated with hydralazine use suggesting that autoantibody production alone is not pathogenic . 3 , 13
Hydralazine-induced vasculitis involves the kidneys in 80 % of cases , often with pauci-immune , crescentic , or necrotizing glomerulonephritis . Less common manifestations include skin , lung , joint , ear , nose , and throat involvement . 3 , 13 A review of 68 cases of hydralazine-induced vasculitis revealed that 62 % were females with a mean age of 64 years and the average exposure duration and dose were 4.7 years and 142mg per day . Kidney involvement occurred in 81 %; skin and lung involvement occurred in 25 % and 19 %, respectively . Nearly all patients were positive for MPO antibodies , ANA , and an anti-histone antibody . 13 If tested , anti-elastase and anti-lactoferrin antibodies and hypocomplementemia are also commonly present , while anti-proteinase 3 and anti-ds DNA antibody are less common . 3 , 4 , 13 In contrast to hydralazine-induced lupus , where most patients improve with hydralazine discontinuation alone , 76 % of patients with vasculitis related to hydralazine required treatment with immunosuppressives . 13 In another report of 10 patients with hydralazine-induced ANCA-associated vasculitis , all received glucocorticoids and eight received cytotoxic therapy , and of these , three required long-term dialysis and two died . 3
Hydralazine-associated pulmonary-renal syndrome is diagnosed by clinical history , serology , and BAL findings consistent with DAH and / or renal biopsy showing pauci-immune glomerulonephritis . Management should include hydralazine cessation , high-dose glucocorticoids , and plasma exchange to remove the causative antibody . In addition , rituximab or cyclophosphamide might be considered , although neither have an immediate effect . 2 DAH is a strong predictor of mortality in idiopathic MPO-vasculitis , with five and 10-year survival rates of 82 % and 68 %, respectively . Most patients with DAH that require renal replacement therapy will remain dialysis dependent . 2
CONCLUSION
Hydralazine use has been increasing , and while drug-induced lupus is a well-known complication , ANCA-associated vasculitis is another rarer and potentially fatal complication of hydralazine use . Providers should be aware that this condition typically manifests years after beginning the drug , and as such , the most important issue is recognition of this possibility and drug cessation when necessary .
REFERENCES
1 . Radić M , Martinović Kaliterna D , Radić J . Drug-induced vasculitis : a clinical and pathological review . Neth J Med . Jan 2012 ; 70 ( 1 ): 12-7 .
2 . West SC , Arulkumaran N , Ind PW , Pusey CD . Pulmonary-renal syndrome : a life threatening but treatable condition . Postgrad Med J . May 2013 ; 89 ( 1051 ): 274-83 . doi : 10.1136 / postgradmedj-2012-131416
3 . Choi HK , Merkel PA , Walker AM , Niles JL . Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis : prevalence among patients with high titers of antimyeloperoxidase antibodies . Arthritis Rheum . Feb
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